Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders.
ABSTRACT Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.
- SourceAvailable from: ncbi.nlm.nih.gov[show abstract] [hide abstract]
ABSTRACT: Genetic testing in Huntington disease, an inherited ultimately fatal neurodegenerative disorder, is infrequent despite wide availability. Factors influencing the decision to pursue testing are largely unknown. We conducted a prospective longitudinal observational study of 1,001 individuals in North America who were at risk for Huntington disease who had not pursued genetic testing prior to enrollment. We evaluated the rationale for remaining untested at baseline, determined the concerns of those who eventually pursued testing, and assessed the population's psychological attributes. We contrasted responses between those who did and did not pursue testing, and between United States and Canadian residents. The principal reasons for remaining untested were comfort with risk and uncertainty and the inability to "undo" knowledge gained. After enrollment, 83 individuals [8.3%] pursued genetic testing. Their greatest concern was losing health insurance, and 41.6% of them [vs. 6.7% of those who did not pursue testing; P < 0.001] reported paying out of pocket for testing or other medical services to conceal their genetic risk from their insurer/employer. Among individuals who were tested, more United States residents [46.1%] than Canadian residents [0.0%; P = 0.02] paid out of pocket for health services or genetic testing. Psychological attributes were similar among individuals who did and did not pursue testing. Individuals at risk for Huntington disease who pursued genetic testing feared losing medical insurance, and many paid out of pocket for medical services. Alleviating the fear of health insurance loss may help those who want to pursue genetic testing for many other conditions. [ClinicalTrials.gov number, NCT0052143].American Journal of Medical Genetics Part A 07/2008; 146A(16):2070-7. · 2.30 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Unintended weight loss frequently complicates the course of many neurodegenerative disorders and can contribute substantially to both morbidity and mortality. This will be illustrated here by reviewing the characteristics of unintended weight loss in the three major neurodegenerative disorders: Alzheimer's disease, Parkinson's disease and Huntington's disease. A common denominator of weight loss in these neurodegenerative disorders is its typically complex pathophysiology. Timely recognition of the underlying pathophysiological process is of crucial importance, since a tailored treatment of weight loss can considerably improve the quality of life. This treatment is, primarily, comprised of a number of methods of increasing energy intake. Moreover, there are indications for defects in the systemic energy homeostasis and gastrointestinal function, which may also serve as therapeutic targets. However, the clinical merits of such interventions have yet to be demonstrated.Journal of Neurology 02/2009; 255(12):1872-80. · 3.58 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The clinical severity of late onset Parkinson's disease (PD) varies from patient to patient and it is further complicated by the increasing prevalence of accompanying disorders in the elderly. We set out to study the impact of ischemic heart disease, minor stroke, hypertension and diabetes mellitus in a group of late onset PD patients (age >or=70 years). Consecutive late onset PD patients seen in the Department of Neurology, Medical School of Patras, Greece were included in this study. We used very strict criteria to eliminate the possibility of including patients with vascular parkinsonism. Comparisons were made between groups of patients suffering with idiopathic Parkinson's disease (IPD) and the above-mentioned diseases. One hundred and sixty-seven consecutive late onset PD patients were included in this study. The most common accompanying disorders in our group were hypertension in 31 (18%) of the patients and minor stroke in 20 (12%). The Hoen and Yahr score in late onset IPD patients who suffered from minor stroke, ischemic heart disease or diabetes mellitus was significantly higher when compared with patients without the above disorders. The results clearly suggest that the presence of vascular disease on an IPD patient may aggravate PD severity. In clinical grounds, these findings can be proved significant since early and aggressive prevention of vascular disease and treatment of vascular risk may contribute in controlling symptom severity in PD.European Journal of Neurology 04/2004; 11(4):231-5. · 4.16 Impact Factor
Current Alzheimer Research, 2012, 9, 5-17
1567-2050/12 $58.00+.00 © 2012 Bentham Science Publishers
Metabolic Dysfunction in Alzheimer’s Disease and Related Neurodegen-
Huan Cai1,#, Wei-na Cong1,#, Sunggoan Ji1, Sarah Rothman2, Stuart Maudsley3 and
1Metabolism Unit, 2Cellular and Molecular Neurosciences Section, 3Receptor Pharmacology Unit, National Institute on
Aging, 251 Bayview Blvd., Suite 100, Baltimore, MD 21224, USA
Abstract: Alzheimer’s disease and other related neurodegenerative diseases are highly debilitating disorders that affect
millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited ef-
ficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many
neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symp-
toms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for ma-
jor neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic
dysregulation in Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, and discuss several potential mecha-
nisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degen-
eration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the
central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in
this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and ‘eumetabolic’ activities
may possess superior efficacies compared to less pluripotent remedies.
Keywords: Neurodegenerative diseases, metabolic dysfunction, bodyweight, diabetes, glucose homeostasis, insulin, leptin,
ghrelin, adiponectin, glucagon-like peptide 1, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease.
process that is subject to modification by a myriad of genetic
and environmental factors. Aging can be defined as the pro-
gressive loss of an organism’s optimal function, which con-
tinues until its eventual failure and death. Aging and many
aging-associated disorders involve perturbed energy balance.
Metabolism, including glucose regulation and appetite bal-
ance, is controlled by both central regulatory inputs (primar-
ily via the hypothalamus) and peripheral signals such as in-
sulin, ghrelin, cholecystokinin, and adipokines (e.g. leptin,
adiponectin, resistin). Alzheimer’s
Huntington’s disease (HD), and Parkinson’s disease (PD) are
debilitating aging-related neurodegenerative disorders, with
severe cognitive and/or motor symptoms that progressively
worsen over time, causing reduced quality of life, increased
medical costs and eventual death. Neurodegenerative dis-
eases mainly affect the middle-aged and elderly and repre-
sent a significant burden on patients and healthcare systems
[1, 2]. Although AD, HD, and PD are neurodegenerative
disorders, current therapies designed to treat these disorders
that target the central nervous system often demonstrate lim-
ited efficacy. Increasing evidence suggests a link between
the incidence and progression of some neurodegenerative
disorders and metabolic dysfunction. Some recent data has
Aging is a highly complex, evolutionarily conserved
*Address correspondence to this author at the Metabolism Unit, National
Institute on Aging, 251 Bayview Blvd., Suite 100, Baltimore, MD 21224,
USA; Tel: (410) 558-8652; E-mail: email@example.com
#These authors contributed equally to the work.
demonstrated that therapies targeted at restoring metabolic
homeostasis may improve cognitive and motor function as
well as increase lifespan in neurodegenerative diseases [3,
4]. Uncontrolled, progressive weight loss and abnormal glu-
cose tolerance are common metabolic dysfunctions observed
in AD, HD, and PD, which appear to negatively impact
overall prognosis through an, as of yet, poorly defined series
of mechanisms [5, 6]. Whether alterations in systemic me-
tabolism are etiologically linked to AD, HD, and PD, or are a
consequence of the disease processes itself is still presently
unclear. However, it is noteworthy that the disease loci of
AD, HD, and PD often involve the hypothalamus, a key
regulatory brain region for global energy homeostasis .
This review will focus on the multiple metabolic risk factors
and disruptions associated with AD, HD, and PD, the
mechanisms of abnormal energy balance in these disorders,
and potential available therapies that could target metabolic
pathways (‘eumetabolic’ agents) to treat neurodegeneration
(see Fig. 1 for overview).
ALZHEIMER’S DISEASE (AD)
States and is the most common form of dementia and cogni-
tive impairment [8-10]. Symptoms of AD include progres-
sive cognitive decline and memory loss, as well as an inabil-
ity to perform routine daily activities. AD progression has
been demonstrated to involve the intricate alterations of
complex protein networks that still need further elucidation
. It is estimated that < 1% of AD cases are caused by rare
genetic variations found in a small number of families, in-
AD is the sixth leading cause of death in the United
6 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
volving chromosome 21 on the gene for amyloid precursor
protein (APP), chromosome 14 on the gene for the preseni-
lin-1 (PS-1), and chromosome 1 on the gene for presenilin-2
(PS-2) . In these inherited forms of AD, often referred to
as ‘early-onset’ AD, symptoms tend to develop before the
age of 65. The vast majority of AD cases however are spo-
radic and therefore lack a simple genetic cause, although
both early-onset and sporadic AD share similar behavioral
symptoms and pathophysiological mechanisms. Progressive
memory loss and reduced cognitive function are associated
with two primary neurodegenerative lesions, accumulations
of beta-amyloid (A?) known as plaques and neurofibrillary
tangles (NFTs) composed of the microtubule protein tau [13-
15]. The generation and accumulation of A? is considered
pivotal for the development of AD , because A? accu-
mulation can set forth a cascade of events, including hyper-
phosphorylation of tau, which in turn results in the formation
of neurofibrillary tangles. Although most cases of AD are
sporadic, alterations in the expression of the lipid-trafficking
molecule, apolipoprotein E4 (ApoE4), has also been demon-
strated to be a genetic risk factor for AD [16, 17]. Interest-
ingly, ApoE4 alterations have also been suggested to be a
risk factor for diabetes and hyperinsulinemia . Despite a
wealth of information concerning AD pathophysiology, the
initial events that trigger A? plaque formation are unclear
and there are currently no effective treatments that can stop
or reverse the AD-related neurodegeneration. The currently
available treatments for AD are only modestly effective, and
some recent clinical trials in AD patients have failed to dem-
onstrate benefit for current medications, or have even indi-
cated harm. Failure to treat AD effectively may be due to the
fact that the mechanisms that cause the disease are not fully
understood, or that existing diagnostic criteria exclude fac-
tors of etiologic importance. It is now clear that disruptions
in metabolism are present in AD and a greater understanding
of these disrupted metabolic pathways may offer new in-
sights into more efficacious treatments for AD.
AD AND BODY WEIGHT
during middle-age is linked to an increased risk of develop-
ing AD. Clinically, obesity (Body Mass Index - BMI greater
than 30) at 40-45 years of age is associated with a 3-fold
increase in the risk of developing AD, while being over-
weight (BMI between 25 and 30) is associated with a 2-fold
increase in AD risk, compared to individuals with a normal
BMI . The Baltimore Longitudinal Study of Aging, a
landmark study of aging and age-related disorders, demon-
strated that among women, being obese in midlife was asso-
ciated with a hazard ratio of 6.57 for AD and among men,
weight gain resulting in a BMI greater than the 90th percen-
tile, between ages 30 and 50, was associated with an in-
creased AD risk . Kivipelto et al. also found similar re-
sults in a cohort of 1449 individuals followed for approxi-
mately 21 years, and midlife obesity was a significant risk
factor for developing AD .
Numerous studies have shown that excess body weight
associated with an increased risk of developing AD. In a
cohort of 299 men and women aged 50-79 years old, in
High BMI and obesity are not the only weight changes
Fig. (1). An overview of some of the relationships between metabolic dysfunction, neurodegenerative disorders, and potential therapies.
Metabolic dysfunction including impaired glucose metabolism, insulin resistance and abnormal appetite regulation are now known to be
comorbid with AD and some other chronic neurodegenerative disorders, such as HD and PD. Treatments that target metabolic malfunctions
may be effective for modifying neurodegenerative-disease pathology and symptoms. IGF-1 (insulin-like growth factor-1); PPARs (perox-
isome proliferator-activated receptors); DPP-4 (dipeptidyl peptidase-4); APP (amyloid precursor protein); PS 1 (presenilin 1); PS 2 (preseni-
lin 2); APOE (apolipoprotein E); ?-SYN (?-synuclein); LRRK2 (leucine-rich repeat kinase 2); UCHL1 (ubiquitin carboxy-terminal hydro-
lase L1) [202, 203].
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 7
which 60 individuals developed AD after 20 years of follow-
up, weight loss of 5 kg or more reliably predicted AD devel-
opment . In contrast, Hughes et al. demonstrated that a
higher baseline BMI and a slower rate of BMI decline were
protective against dementia . It is unclear exactly why
excess body weight in midlife represents a risk factor for
developing AD later in life, whereas in old age it appears to
be protective. It must be noted however, that most studies
use non-specific measures of body composition, such as total
body weight and BMI (calculated as weight in kilograms
divided by height in meters squared), rather than specific
measures of body fat and muscle mass composition. Normal
aging is associated with increases in body fat and decreases
in lean muscle mass, therefore non-specific adiposity meas-
ures, such as BMI, may have limited accuracy when describ-
ing the relationship between body weight and the risk of de-
veloping AD. Yet, the studies summarized previously still
strongly suggest a link between obesity, global energy regu-
lation, and AD pathogenesis, which needs to be further elu-
cidated in order to fully understand AD pathology.
ALTERATIONS IN BRAIN GLUCOSE METABOLISM
of developing AD and excess body weight in midlife reflects
a diet high in simple sugars and fats and a sedentary lifestyle.
A recent study showed that adherence to a ‘Mediterranean
diet’ and intense physical exercise can be protective against
AD . Similarly, reducing caloric intake increases health-
span, reduces damage in the brain due to aging, and provides
greater maintenance of various brain functions, potentially
through ‘hormetic’ mechanisms [25-28]. Experimental re-
sults indeed can corroborate clinical findings, as it has been
shown that rats fed a high-fat/glucose diet, to induce insulin
resistance, were found to exhibit impaired spatial learning
ability, reduced hippocampal dendritic spine density, and
reduced long-term potentiation in the CA1 region . Glu-
cotoxicity, or disrupted insulin signaling, are two of the po-
tential mechanisms thought to mediate changes in hippo-
campal function observed from a high-fat diet, implying that
diet-induced insulin resistance/ hyperinsulinemia may be one
of the links between obesity and AD. Epidemiological stud-
ies have indicated an association between type 2 diabetes
mellitus (DM) and an increased risk of developing AD. The
Rotterdam study, the first of its kind to probe for a connec-
tion between type 2 DM and AD, revealed an approximate
two-fold increase in risk of developing AD in patients with
diabetes, compared to patients without the condition .
Furthermore, in the same study, DM requiring insulin treat-
ment was associated with a four-fold increase in incidence of
AD. The presence of type 2 DM and the ApoE4 allele to-
gether has also been shown to increase the risk of developing
AD, to more than five-fold, compared to individuals without
those two conditions . Additionally, Luchsinger et al.
demonstrated that hyperinsulinemia is associated with a dou-
bled risk of developing AD . Moreover, a thorough re-
view of a registry of AD patients revealed that 80% had ei-
ther type 2 DM or impaired fasting glucose measurements
Abnormal glucose homeostasis is linked to cognitive
dysfunction in such that patients with either type 1 or type 2
It is possible that the association between increased risk
DM display significant memory impairment and attention
deficits on cognitive testing compared to control subjects
. Hyperglycemia increases the number of mental subtrac-
tion errors in individuals with diabetes  and poor glyce-
mic control (as evidenced by high hemoglobin A1C levels),
has been associated with low scores on neuropsychological
testing . There are a number of mechanisms through
which dysglycemia can lead to cognitive dysfunction. Hy-
perglycemia can lead to the activation of the polyol pathway,
formation of advanced glycation end products, activation of
protein kinase C, increased glucose shunting in the hexosa-
mine pathway, and it is also possible that the increase in re-
active oxygen species (ROS) associated with these mecha-
nisms are then, in-part, responsible for altered brain function
[36-38]. In animal models, global alterations in functional
neurotransmission have also been linked to hyperglycemia,
including abnormal N-methyl-D-aspartate (NMDA), acetyl-
choline, serotonin, dopamine and norepinephrine neuro-
transmission [39-42]. Whether these abnormalities lead to
irreversible neuronal damage is presently unclear. There is
also evidence that hyperglycemia may directly contribute to
the pathophysiology of AD. Administration of high amounts
of glucose can induce tau cleavage and apoptosis, and db/db
mice, which are commonly used to model DM, exhibit an
increase in tau phosphorylation compared to controls .
Although the exact mechanism is not entirely known, nu-
merous reports therefore support the notion that metabolic
dysfunction may worsen neurodegeneration in AD patients.
METABOLIC HORMONES AND THEIR THERA-
PEUTIC POTENTIAL IN AD
Insulin and AD
signaling dysfunction in AD. Insulin receptors are abundant
in many brain regions, including the hippocampus, although
the physiological role of insulin in the brain is not fully un-
derstood [44, 45]. Insulin is now believed to influence re-
gional glucose metabolism, as evidenced by rodent studies
and one human study utilizing PET imaging [46-49]. Many
studies have also shown that insulin plays a role in regulating
learning and memory processes [50-52]. Clinically, there is a
higher density of insulin receptors in the brain of AD pa-
tients compared to control subjects, possibly reflecting
upregulation of the receptor in an attempt to compensate for
the decreased functionality of insulin . Furthermore, hy-
perinsulinemia (a marker of insulin resistance in the meta-
bolic disease spectrum) can decrease the availability of insu-
lin degrading enzyme (IDE), which is essential for the deg-
radation and clearance of A? in the brain . Additionally,
mouse models of type 1 and type 2 DM are associated with
increased tau phosphorylation, which is likely secondary to
It is therefore likely that therapies that manipulate insulin
signaling may be beneficial for treating the neurological
symptoms of AD. Peroxisome proliferator-activated recep-
tors (PPARs), which belong to the steroid, thyroid and reti-
noid receptor superfamily, are ligand-inducible transcription
factors. The PPARs subfamily is comprised of three iso-
forms: PPAR?, PPAR?/? and PPAR?. Two PPAR? agonists,
pioglitazone and rosiglitazone, are currently widely pre-
Recent work has begun to outline the presence of insulin
8 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
scribed for the treatment of type 2 DM. PPAR? agonists im-
prove both lipid and glucose metabolism, mainly by increas-
ing peripheral insulin sensitivity, which ameliorates the
metabolic dysfunction brought on by the diabetic patho-
physiology . There is increasing evidence demonstrating
the efficacy of PPAR? agonists for the treatment of AD.
PPAR? activation suppresses the expression of inflammatory
genes, which, clinically, has been shown to ameliorate neu-
rodegeneration . Experimentally, treatment with PPAR?
agonists has been associated with both reduced A? plaque
load and improved behavioral outcomes in an animal model
of AD . Clinical studies have corroborated this finding;
i.e. treatment with a PPAR? agonist reduces disease-related
pathology, improves learning and memory, and enhances
attention in AD patients . The cyclooxygenase inhibitor
Ibuprofen (iso-butyl-propanoic-phenolic acid), which can
activate PPAR?, has been demonstrated to significantly re-
duce amyloid pathology and reduce microglial-mediated
inflammation in a mouse model of AD, potentially via
PPAR? signaling [58, 59]. In addition, PPAR? agonists have
been shown to reduce A? plaque burden and A?42 (a specifi-
cally toxic form of A?) levels in the brain by approximately
20-25%, restore insulin responsiveness and lower glucocorti-
coid levels in mouse models of AD [60, 61]. These results
suggest that PPAR? agonists may be useful for the treatment
of AD, a hypothesis greatly strengthened by both experimen-
tal and clinical studies demonstrating that rosiglitazone can
attenuate learning and memory deficits in AD [3, 61, 62]. It
is worth noting that PPAR? also transcriptionally induces
IDE expression, which could explain the effectiveness of
PPAR? agonists in treating both type 2 DM and AD .
PPAR?, which is expressed at higher levels in the brain than
PPAR?, also plays a role in regulating lipid and glucose me-
tabolism. In a recent study, treatment with the PPAR? ago-
nist, GW742, reduced amyloid burden, an effect thought to
be mediated by alterations in amyloid clearance . Current
data suggest that insulin and its downstream signaling cas-
cades play an important role in AD pathogenesis. It is un-
clear whether treatments that target insulin signaling demon-
strate efficacy due to direct or indirect mechanisms, because
insulin directly affects the brain and a systemic metabolic
dysfunction is often co-morbid with AD. Nevertheless, these
studies provide convincing evidence that the insulin signal-
ing pathway may be a novel therapeutic target for the treat-
ment of AD.
Leptin and AD
plays a pivotal role in the control of food intake, body
weight, fat storage, immune system function, reproductive
function, insulin sensitivity, and neuronal protection [65-67].
Obesity is associated with leptin resistance/hyperleptinemia
in addition to insulin resistance. Within the central nervous
system, leptin crosses the blood-brain-barrier to bind to spe-
cific receptors in the hypothalamus to mediate food intake,
body weight and energy expenditure . A small number of
studies have begun to outline a potential connection between
abnormal leptin levels and AD. AD patients with significant
weight loss display lower plasma leptin levels than weight-
stable AD patients, and disruption of homeostasis between
Leptin, which is primarily synthesized in adipose tissue,
leptin and cortisol is also observed in some AD patients [69,
70]. In the Framingham study, a landmark longitudinal
study, lower plasma leptin levels were associated with a
higher risk of incident AD, corresponding to an absolute risk
over a 12-year follow-up of 25% for persons in the lowest
quartile versus 6% in the highest . Leptin may be directly
involved in the development of AD symptoms by exerting
effects on the brain, as high expression of leptin receptors are
found in the hippocampus, suggesting that leptin plays a role
in controlling learning and memory. Indeed, leptin has been
shown to be crucial for the maintenance of normal hippo-
campal synaptic plasticity [72, 73]. Impairments in long-term
potentiation in the CA1 region of the hippocampus and poor
spatial memory compared to controls, are noted in leptin
receptor-deficient rodent models, implying an involvement
of leptin and/or its receptor in normal memory function .
If leptin is indeed required for normal hippocampal function,
it stands to reason that it may represent a reasonable thera-
peutic target for AD, a disease in which the hippocampus is
particularly vulnerable. These data indicate that leptin - be-
sides its role in energy regulation - may directly regulate the
behavioral and pathological progression of AD. Leptin is
structurally and functionally similar to a class of signaling
molecules known as proinflammatory cytokines, and it plays
a regulatory role in innate and adaptive immunity . AD
pathogenesis in the brain includes overexpression of cytoki-
nes and upregulation of the innate immune system. Multiple
studies have shown that manipulating leptin levels can ame-
liorate AD pathology by affecting A? plaques. Leptin treat-
ment can promote A? clearance by reducing ?-secretase ac-
tivity and increasing ApoE-dependent A? uptake , and it
also improves memory performance in AD animal models.
Leptin can also reduce tau phosphorylation through inactiva-
tion of GSK-3? . AMP-activated protein kinase (AMPK)
is emerging as a central modulator of the major pathological
hallmarks of AD in the brain, and leptin deficiency in AD
can contribute to down-regulation of the AMPK system,
causing increases in A? and phosphorylated tau [78, 79]. As
leptin appears to play a significant functional role in the pro-
gression of AD, a growing body of evidence supports the use
of leptin-modifying drugs to treat AD. Leptin administration
improves memory in SAMP-8 mice, an accelerated senes-
cence rodent model that develops amyloid plaques .
Chronic leptin treatment has also been shown to significantly
reduce the levels of A? and phosphorylated tau without an
untoward inflammatory reaction in two different transgenic
models of AD [76, 81]. These biochemical and pathological
changes were also correlated with behavioral improvements,
suggesting that leptin not only reduces AD pathology but
also ameliorates cognitive symptoms . Direct administra-
tion of leptin into the brain has been observed to facilitate
hippocampal long-term potentiation and improve memory
performance in mice . Thus, abnormal leptin signaling -
either as a consequence of leptin resistance or secondary to
reduced leptin levels - may be one of the primary mecha-
nisms underlying hippocampal dysfunction in AD. The stud-
ies summarized here suggest that leptin could also serve as a
therapy that increases learning and memory capacity in AD
patients and reduces A? plaques in the brain, while helping
maintain adequate metabolic control.
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 9
Ghrelin and AD
assists in the promotion of sensations of hunger . While
its interactions with the neurons of lateral, paraventricular,
and arcuate nuclei of the hypothalamus to regulate energy
balance and growth hormone release have been well docu-
mented , recent evidence suggests that ghrelin also binds
to and activates the ghrelin receptors expressed on the py-
ramidal neurons of layer V in the sensorimotor area and in
the cingulate gyrus of the cerebral cortex . Furthermore,
studies have demonstrated that ghrelin, in addition to its role
in promoting energy intake, may also affect cognition as
well. Carlini et al. demonstrated that intracerebroventricular
(i.c.v.) injections of ghrelin increased memory retention in
rats . This group also showed that ghrelin potentiates a
dose-dependent increase in memory retention, with the
maximal effect occurring in the hippocampus . It was
recently shown that circulating ghrelin binds to neurons of
the hippocampal formation, promoting dendritic spine for-
mation and generation of long-term potentiation (LTP) .
Targeted disruption of ghrelin signaling resulted in a de-
creased number of spine synapses in the stratum radiatum
and impaired performance in behavioral memory testing,
both of which were rapidly restored by ghrelin administra-
tion . These data strongly support a role for ghrelin sig-
naling in maintaining normal memory function and provide a
motivation for the study of ghrelin regulation in AD. Clinical
studies have indicated a role for ghrelin in various metabolic
disorders as well as AD [88, 89]. Ghrelin levels in the brain
are altered in some Alzheimer’s patients, suggesting that
changes to the ghrelin signaling system may indeed contrib-
ute to AD pathophysiology . Recently, two non-peptide
ghrelin receptor agonists (GSK894490A and CP-464709-18)
were shown to significantly improve performance in the
novel object recognition and modified water maze tests in
male Lister hooded rats, indicating the potential of ghrelin
for treating cognitive dysfunction . These studies suggest
that ghrelin plays a vital role in not only regulating metabolic
control, but also in regulating cognitive function and mem-
ory capacity, and that abnormal ghrelin signaling could be
caused by, and/or worsen AD and its symptomology [92,
Ghrelin is a hormone produced by the stomach which
Adiponectin and AD
by adipose tissue, is a hormone that plays a role in regulating
insulin sensitivity and energy expenditure . Targeted
deletion of the adiponectin gene can lead to insulin resistance
, and continuous systemic infusion of adiponectin can
enhance insulin sensitivity in type 2 diabetic mice . Adi-
ponectin abnormalities have been implicated in various
metabolic disorders [97-99], all of which could also act as
risk factors for the development of AD . Recent studies
have shown that the adiponectin receptors AdipoR1 and
AdipoR2 are expressed throughout the central nervous sys-
tem (CNS) . However, there is still some debate about
whether adiponectin crosses the blood-brain-barrier or not
[102, 103]. Few studies to date have focused on a potential
correlation between adiponectin and AD. Recently, one
clinical study demonstrated that some AD patients have ele-
vated levels of adiponectin in both plasma and cerebrospinal
Adiponectin, the most abundant adipocytokine secreted
fluid (CSF) , suggesting that it may play a role in medi-
ating AD progression, possibly through its effects on periph-
eral or brain metabolism. It is also noteworthy that elevated
interleukin-6 has been detected in the brains of some AD
patients [105, 106], and that treatment with adiponectin can
reduce the secretion of the centrally active interleukin-6 from
brain endothelial cells . Due to its relatively recent dis-
covery, there are currently no known clinical trials of adi-
ponectin modifying drugs related to AD therapy. However, it
is likely that adiponectin system-targeted compounds could
offer potential as therapeutic targets for the metabolic com-
ponent of AD due to its well documented role in diabetes and
other metabolic disorders [99, 107].
Glucagon-Like Peptide 1 and AD
islet beta-cell proliferation and glucose-dependent insulin
secretion, lowers blood glucose and food intake, and is an
effective incretin-based therapy for type 2 DM . GLP-1
and its cognate receptor are both expressed throughout the
brain and stimulation of this system appears to be neuropro-
tective and can reduce neuronal degeneration in various ani-
mal models [4, 109, 110]. A body of literature suggests the
potential therapeutic relevance of GLP-1 to CNS disorders
such as AD . GLP-1 and exendin-4, a natural and stable
long-acting analogue of GLP-1, possess neurotrophic proper-
ties and protect neurons against A? and oxidative insults
. GLP-1 can reduce amyloid-beta peptide levels in vivo
and decreases levels of amyloid precursor protein in cultured
neuronal cells, implying that GLP-1 could be effective at
reducing plaque load in AD . In addition, GLP-1 recep-
tor agonists protect neurons against A? and glutamate-
induced apoptosis in cells and attenuate cholinergic neuron
atrophy in the basal forebrain of the rat following an excito-
toxic lesion . A recent study using GLP-1 receptor
knock-out mice demonstrated that GLP-1 receptor signaling
can play an important role in the control of synaptic plastic-
ity . The novel GLP-1 analogue (Val8(GLP-1)) has also
been shown to enhance synaptic plasticity and to reverse the
impairment of long-term potentiation (LTP) induced by A?
fragments, further strengthening the hypothesis that GLP-1
may be useful for treating AD . Other stable GLP-1
analogues such as Liraglutide, Asp7GLP-1, N-glyc-GLP-1,
and Pro9GLP-1 were recently found to have facillitatory ef-
fects on LTP by the same group . Additionally, the
novel long-acting GLP-1 analogue GLP-1/Tf (GLP-1 fused
to transferrin) potentially also shows promise for the treat-
ment of metabolic dysfunction in AD . Attenuation of
the activity levels of dipeptidyl peptidase 4 (DPP-4, the en-
zyme that cleaves and inactivates GLP-1), can stabilize the
plasma levels of the bioactive GLP-1. A recent study has
demonstrated that sitagliptin, a DPP-4 inhibitor, could sig-
nificantly delay some forms of AD pathology, including
amyloid deposition, when administrated early in the disease
course in a mouse model of AD .
Glucagon-like peptide 1 (GLP-1) enhances pancreatic
Brain-Derived Neurotrophic Factor and AD
tein, is a member of the family of neutrophins . Besides
its well-established roles in neuronal development, neuronal
maintenance and survival as well as promoting synaptic plas-
Brain-derived neurotrophic factor (BDNF) a 13-kDa pro-
10 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
ticity, BDNF also plays a considerable role in regulating
global metabolic function. BDNF deficiency in rodents leads
to hyperphagia, obesity, hyperinsulinemia, and hyperlepti-
nemia [120, 121]. There is also evidence that BDNF defi-
ciency in humans can lead to metabolic dysfunction .
BDNF signaling has been shown to be impaired in AD,
which could be relevant considering the neurological and
metabolic abnormalities noted in AD. Studies have demon-
strated low brain BDNF mRNA expression in patients with
AD, including the hippocampus , neocortex and in the
nucleus basalis of Meynert [124-126]. A recent study on the
role of BDNF in AD investigated the sorting protein-related
receptor with A-type repeats (SORLA). SORLA regulates
APP intracellular trafficking and processing into A?, and
when overexpressed, can reduce amyloid plaque formation
[127, 128]. BDNF was found to be a major inducer of
SORLA gene transcription through the extracellular regu-
lated kinase (ERK) pathway . Circulating plasma
BDNF levels have been shown to associate with multiple
cardiovascular markers of age-related pathophysiology and
also to significantly decrease with age , and it is there-
fore possible that a gradual decrease in BDNF levels may
contribute to the increase in the risk of developing AD with
METABOLIC DYSFUNCTION IN HUNTINGTON’S
disorder that affects approximately 5-7 individuals per
100,000 . The disease is characterized by progressive
chorea, dystonia, cognitive dysfunction and psychiatric and
behavioral symptoms . Individuals with HD usually
become symptomatic between the fourth and fifth decades of
life and invariably die from complications of the disease
within one to two decades after initial diagnosis . The
neuropathologic hallmarks of HD include severe cell loss
and atrophy in the caudate and putamen . The underly-
ing genetic defect in HD is the presence of expanded repeats
of the trinucleotide CAG in exon 1 of the HD gene, which
encodes for the protein huntingtin . Huntingtin (htt) is
expressed ubiquitously in mammalian cells but its specific
functions are not fully understood. Htt is believed to influ-
ence a number of cellular functions, including BDNF expres-
sion, vesicle trafficking, axonal transport and transcriptional
regulation [136-139]. The genetic defect that leads to the
development of HD causes the formation of a mutant form of
huntingtin, which contains polyglutamine expansions that
make the protein more susceptible to a pathological prote-
olysis process that generates cytotoxic amino-terminal htt
fragments and also promotes subsequent aggregation of the
remaining htt protein . Aggregates of mutant huntingtin
appear to be neurotoxic, as they interfere with the normal
function of several nuclear and cytoplasmic proteins that
regulate transcription, apoptosis, mitochondrial function and
axonal transport [141-144]. Postmortem brains of HD pa-
tients demonstrate reduced BDNF levels in the caudate and
putamen, whereas wild-type htt stimulates BDNF gene tran-
scription through promoter II activation [145-147]. In the
presence of mutant htt, a transcriptional repressor inhibits
BDNF gene transcription [146, 148]. In addition, as men-
tioned above, mutant htt may also interfere with BDNF vesi-
Huntington’s disease is an autosomal dominant genetic
cle transport . Mutant htt aggregates are also found out-
side of the central nervous system, and animal studies sug-
gest that these aggregates can cause cell toxicity in periph-
eral organs as well. For example, in the R6/2 and N171-82Q
mouse models of HD, mutant htt aggregates are present in
pancreatic islet cells [150, 4], and these HD mice display
decreased pancreatic beta-cell mass and exhibit impaired
HD and Body Weight
[151-153]. Patients with clinical HD and presymptomatic
gene carriers typically have a lower BMI than control sub-
jects . Although poor dietary intake from severe
dysphagia can occur in HD, weight loss is common in pa-
tients who have an intact appetite and high caloric intake
[155, 156]. Total energy expenditure is higher in HD patients
compared to controls, which in part reflects their present
hyperkinetic state (chorea and dystonia) [157-159]. While
hyperkinesis appears to be an important contributing factor,
it does not entirely account for all weight loss observed in
HD. A cross-sectional study of individuals with early-stage
HD showed that BMI was significantly lower in HD patients
than control subjects and that neither disease duration,
dystonia, nor chorea scores were significantly associated
with BMI . If indeed hyperkinesis is not a sine qua non
for weight loss in HD, it has been speculated that HD pa-
tients experience increased energy expenditure, secondary to
a hypermetabolic state. A recent study demonstrated that
clinically unaffected individuals with a CAG repeat length
greater or equal to 37 required an increased caloric intake to
maintain their BMI compared to individuals with less than
37 CAG repeats , suggesting a deficit in energy homeo-
stasis not accounted for by excessive motor activity. In addi-
tion, among a group of 517 patients with early stage HD fol-
lowed for 3 years, a higher CAG repeat number was associ-
ated with a lower initial mean BMI and faster rate of BMI
decline . Increasing numbers of CAG repeats correspond
to increased disease severity, indicating more substantial
aggregation of mutant htt in central and peripheral organs
involved in energy regulation. Post-mortem studies in HD
patients have demonstrated neuronal loss in regions of the
hypothalamus involved in energy balance, including both the
paraventricular and ventromedial nuclei. Although the hypo-
thalamus plays an important role in energy regulation, attrib-
uting a high rate of energy expenditure to the presence of
aggregates in the hypothalamus is too simplistic. Direct dele-
terious effects of mutant htt on peripheral tissues are likely to
contribute to the dysregulation of the energy balance system.
Abnormalities in key metabolic tissues such as adipose tissue
[161, 162], pancreas [163, 164], and skeletal muscle [165,
166] have all been described in mouse models of HD. Fur-
thermore, Mochel et al. demonstrated that HD patients with
weight loss have lower levels of the branched chain amino
acids, valine, leucine, and isoleucine, suggesting a critical
need for Krebs cycle energy substrates , and reflecting
mitochondrial dysfunction. Additionally, Popovic et al.
found high plasma ghrelin and low plasma leptin in HD pa-
tients (~ 6 years of disease duration) compared with healthy
controls, indicating a state of negative energy balance .
Low leptin levels have also been noted in a mouse model of
Weight loss is a well-recognized manifestation of HD
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 11
HD , suggesting that metabolic hormones are an important
aspect of the energy dysregulation observed in HD.
HD and Altered Glucose Homeostasis
increased risk for the development of type 2 DM . In
one study, seven out of 14 patients with documented HD
demonstrated an abnormal response in standard glucose tol-
erance tests . Additionally, some HD patients with
normal glucose tolerance can still display an increase in insu-
lin resistance . Glycosuria and glucose intolerance de-
velop in mouse models of HD beginning as early as 9 weeks
and as mentioned above, these mice also express mutant htt
aggregates in the pancreas, implying that mutant htt pathol-
ogy can also mediate metabolic dysfunction . Therefore
it has been suggested that an effective treatment for HD
should target the symptoms that affect the entire body, in-
cluding the loss of motor coordination and dysglycemia
. In addition to directly impairing insulin secretion due
to the formation of aggregates in the pancreas, mutant htt
may also affect insulin resistance via pathophysiological
functionality of the hypothalamus . Blockade of hypotha-
lamic insulin receptors by phosphoinositide 3-kinase inhibi-
tors leads to hepatic insulin resistance and increased hepatic
glucose production, implying that the hypothalamus is nec-
essary for normal insulin signaling . Martin et al. dem-
onstrated that treatment with insulin failed to correct hyper-
glycemia, although treatment with exendin-4, a drug com-
monly used for the treatment of type 2 DM, improved the
glycemic profile and reduced mutant huntingtin aggregates
in both the brain and pancreas, while also prolonging
lifespan in a mouse model of HD . These findings suggest
that targeting the peripheral metabolic dysfunction observed
in HD could be beneficial for treating some aspects of this
disorder, and further support the notion that new treatments
that target the entire body - rather than just the CNS – are
likely to be more effective for treating HD.
Studies have found an association between HD and an
METABOLIC DYSFUNCTION IN PARKINSON’S
ment disorder, only slightly less prevalent than AD, that usu-
ally affects individuals in their sixth decade of life .
Classical PD symptoms include bradykinesia, resting tremor,
rigidity, and gait instability. Pathologically, PD is character-
ized by a profound neuronal loss in the pars-compacta of the
substantia nigra. In addition, in PD there is often an accumu-
lation of ubiquinated protein deposits in the cytoplasm of
neurons (Lewy bodies) and neurites (Lewy neurites), usually
containing aggregates of the protein ?-synuclein [175-177].
Low levels of BDNF have been observed in the substantia
nigra pars compacta of PD patients compared to controls and
experimentally, two pathogenic mutations linked to ?-
synuclein have been associated with a loss of BDNF synthe-
sis in rodents [124, 178]. Furthermore, mice with a condi-
tional deletion of BDNF in the midbrain and hindbrain have
been shown to exhibit reduced numbers of dopaminergic
neurons in the substantia nigra , indicating that BDNF
is necessary for normal development of those neurons.
Parkinson’s disease (PD) is a neurodegenerative move-
PD and Body Weight
general, individuals with PD possess a lower BMI than age-
matched controls [180, 181]. PD patients lose weight in the
years preceding their diagnosis and continue to lose weight
thereafter . While impaired hand-mouth coordination,
dysphagia, and hyposmia have been listed as contributing
factors, there is some debate over whether decreased energy
intake is a significant contributor to the weight loss observed
in PD [182, 183]. Levi et al. and Markus et al. observed an
increased resting energy expenditure in PD patients, com-
pared to healthy controls, using indirect calorimetry [184,
185]. However Toth et al. reported a lower daily energy ex-
penditure in PD patients using double-labeled water tech-
nique . A recent study using double-labeled water to
measure daily energy expenditure in PD patients displaying
weight loss or a stable-weight found no significant energetic
difference between the two groups . Unlike AD, obesity
is not considered to be a risk factor for PD development
[187, 188]. However, at least one study reported that in a
cohort of over 10,000 men, subjects who lost at least 0.5
units of BMI in the decade following college entry had a
significantly increased risk of developing PD compared with
individuals with stable weight. It is unclear however if the
weight loss during young adulthood seen in the study repre-
sented an early manifestation of PD. Leptin tends to be low
in PD patients who experience weight loss, which may re-
flect a decrease in body fat. Evidente et al. found a trend
towards low plasma leptin levels in PD patients with unin-
tended weight loss . These results were corroborated by
another study that demonstrated that PD patients who lost
body weight possessed lower serum leptin levels than
weight-stable PD patients . In addition to lower plasma
leptin levels, lower plasma ghrelin levels were also noted in
PD patients who experienced weight loss . While low
plasma leptin is expected to accompany loss of body fat, the
finding of low plasma ghrelin is less intuitive and warrants
further investigation. A recent study showed that peripheral
ghrelin is neuroprotective for nigrostriatal dopamine function
through activation of UCP2-dependent alterations in mito-
chondrial respiration . Additionally, ghrelin or ghrelin
receptor knockout mice are more susceptible to dopaminer-
gic neuron loss in the substantia nigra and striatum after
MPTP treatment, suggesting that abnormal ghrelin signaling
may represent a predisposing factor for nigrostriatal dopa-
Weight loss is a well-recognized manifestation of PD. In
PD and Altered Glucose Homeostasis
glycemia and abnormal glucose tolerance in patients with PD
[193, 194]. However, there is some debate regarding a direct
association between PD and type 2 DM. One large epidemi-
ologic study, which utilized the UK-based General Practice
Research Database (GPRD) which contains computerized
medical records of over 5 million people, found that the
prevalence of diabetes was similar in patients with and with-
out PD. Furthermore, the study concluded that the risk of
developing diabetes was lower in PD patients than in sub-
jects without PD . A second major epidemiological
Recent studies have demonstrated the presence of dys-
12 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
study, the Physician’s Health Study, which includes a cohort
of U.S. male physicians, indicated that although individuals
with diabetes had an increased risk of developing PD, the
highest risk was found in individuals with short-duration,
older-onset diabetes without complications. Thus, it is pres-
ently unclear whether diabetes increases the likelihood of
developing PD and further studies are therefore needed to
investigate a potential link. There is also some evidence for
abnormal insulin signaling in PD. Although insulin receptors
are normally abundant in the substantia nigra, some PD pa-
tients display a loss of insulin receptors in this brain region
[196, 197]. In rat models with streptozotocin-induced diabe-
tes, low levels of insulin have been associated with de-
creased amounts of dopamine transporter mRNA and tyro-
sine hydroxylase mRNA in the substantia nigra .
Moreover, increased insulin receptor substrate-2 phosphory-
lation, a sign of insulin resistance, has been observed in the
dopamine-depleted striatum in PD .
age-dependent, but accelerated, manner. All of these disor-
ders display accumulation of products of oxidative reactions
which lead to wide-spread lipid and protein damage .
These neurodegenerative disorders mimic advanced aging on
multiple levels, including cognitive and motor decline as
well as molecular signaling defects such as impaired insulin
signaling. It is striking that all three disorders display a
metabolic dysfunction phenotype in conjunction with a neu-
rodegenerative pathology. While damage to the hypothala-
mus via abnormal protein aggregates, such as mutant htt or
A? plaques, may be part of the cause of energy dysregula-
tion, hypothalamic disease on its own does not explain the
whole process entirely. A more complete and acceptable
hypothesis that explains the metabolic changes combined
with neuronal damage in these diseases includes a descrip-
tion of a disrupted connection between peripheral organs that
manage energy regulation and the CNS through alterations in
leptin, ghrelin, GLP-1 and insulin signaling. Although these
metabolic hormones are traditionally thought to be involved
primarily in metabolic disorders, it is now clear, as discussed
above, that alterations in these hormones can have severe
implications for the etiology of several prominent neurode-
generative disorders. Furthermore, it is also clear that thera-
peutic targets that manipulate these metabolic factors are
showing promise for the treatment of neurodegenerative dis-
orders (see Fig. 1 for overview). Current research is starting
to suggest that successful treatments for neurodegenerative
disorders should ideally target the whole body, rather than
focusing on the CNS alone. It is likely that multiple endocri-
nological factors play a combinatorial role in facilitating AD,
HD, and PD pathophysiology; hence, studies that attempt to
understand the overall effects of the combination of these
hormones, rather than just the individual, are necessary
. It is important to note that many animal studies are
confounded by a series of factors, including housing condi-
tions and diet, that can make these subjects more prone to
developing metabolic dysfunctions and cause challenges in
ascertaining whether the metabolic phenotype is associated
with the disease progression or with the animal’s lifestyle
. In order to better understand disease processes and bet-
AD, PD and HD all represent diseases that progress in an
ter serve patients, we must attempt to design studies that look
into combinatorial effects of metabolic hormones and neu-
ronal signaling molecules in accurate animal models, allow-
ing us to characterize and discover the potential that meta-
bolic factors hold, in treating both metabolic disorders and
various neurodegenerative diseases.
CONFLICT OF INTEREST
Program of the National Institute on Aging, National Insti-
tutes of Health. The authors have no conflicts of scientific
interest with respect to the manuscript.
This research was supported by the Intramural Research
A? = Beta-amyloid
AD = Alzheimer’s disease
AMP-activated protein kinase
APP = Amyloid precursor protein
Brain-derived neurotrophic factor
Body Mass Index
CNS = Central nervous system
DPP4 = Dipeptidyl peptidase-4
Extracellular regulated kinase
Glucagon-like peptide 1
= General Practice Research Database
Glycogen synthase kinase-3?
Huntington’s disease =
htt = Huntingtin
Insulin degrading enzyme
Insulin-like growth factor-1
LRRK2 = Leucine-rich repeat kinase 2
NFTs = Neurofibrillary tangles
PPARs = Peroxisome proliferator-activated receptors
ROS = Reactive oxygen species
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 13
SORLA = Sorting protein-related receptor with A-type
Ubiquitin carboxy-terminal hydrolase L1
Uncoupling protein 2 =
 Alzheimer’s Association. 2010 Alzheimer's disease facts and fig-
ures. Alzheimer's and Dementia 6:158-94 (2010).
Oster E, Dorsey ER, Bausch J, Shinaman A, Kayson E, Oakes D, et
al. Fear of health insurance loss among individuals at risk for
Huntington disease. American Journal of Medical Genetics Part A
Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR,
Asthana S, et al. Preserved cognition in patients with early Alz-
heimer disease and amnestic mild cognitive impairment during
treatment with rosiglitazone: a preliminary study. Am J Geriatr
Psychiatry 13:950-8 (2005).
Martin B, Golden E, Carlson OD, Pistell P, Zhou J, Kim W, et al.
Exendin-4 Improves Glycemic Control, Ameliorates Brain and
Pancreatic Pathologies, and Extends Survival in a Mouse Model of
Huntington's Disease. Diabetes 58:318-28 (2009).
Aziz N, van der Marck M, Pijl H, Olde Rikkert M, Bloem B, Roos
R. Weight loss in neurodegenerative disorders. J Neurol 255:1872-
Papapetropoulos S, Ellul J, Argyriou AA, Talelli P, Chroni E,
Papapetropoulos T. The effect of vascular disease on late onset
Parkinson's disease. Eur J Neurol 11:231-5 (2004).
Standaert DG, Lee VM, Greenberg BD, Lowery DE, Trojanowski
JQ. Molecular features of hypothalamic plaques in Alzheimer's dis-
ease. Am J Pathol 139:681-91 (1991).
Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alz-
heimer Disease in the US Population: Prevalence Estimates Using
the 2000 Census. Arch Neurol 60:1119-22 (2003).
Ashford J. APOE genotype effects on alzheimer’s disease onset
and epidemiology. J Mol Neurosci 23:157-65 (2004).
Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic
duo in age-related neuronal plasticity and neurodegenerative disor-
ders. Trends Neurosci 27:589-94 (2004).
Martin B, Brenneman R, Becker KG, Gucek M, Cole RN, Maud-
sley S. iTRAQ Analysis of Complex Proteome Alterations in
3xTgAD Alzheimer's Mice: Understanding the Interface between
Physiology and Disease. PLoS ONE 3:e2750 (2008).
Selkoe DJ. Alzheimer's Disease--Genotypes, Phenotype, and
Treatments. Science 275:630-1 (1997).
Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M. Genetic dis-
section of Alzheimer's disease and related dementias: amyloid and
its relationship to tau. Nat Neurosci 1:355-8 (1998).
Hardy J, Selkoe DJ. The Amyloid Hypothesis of Alzheimer's Dis-
ease: Progress and Problems on the Road to Therapeutics. Science
Maudsley S, Mattson MP. Protein twists and turns in Alzheimer
disease. Nat Med 12:392-3 (2006).
Mahley RW. Apolipoprotein E: cholesterol transport protein with
expanding role in cell biology. Science 240:622-30 (1988).
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M,
Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity bind-
ing to beta-amyloid and increased frequency of type 4 allele in late-
onset familial Alzheimer disease. Proc Natl Acad Sci USA
Peila R, Rodriguez BL, Launer LJ. Type 2 Diabetes, APOE Gene,
and the Risk for Dementia and Related Pathologies: The Honolulu-
Asia Aging Study. Diabetes 51:1256-62 (2002).
Whitmer RA, Gunderson EP, Quesenberry CP, Jr., Zhou J, Yaffe
K. Body mass index in midlife and risk of Alzheimer disease and
vascular dementia. Curr Alzheimer Res 4:103-9 (2007).
Zonderman AB. Predicting Alzheimer's disease in the Baltimore
longitudinal study of aging. J Geriatr Psychiatry Neurol 18: 192-5
 Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I,
Winblad B, et al. Obesity and Vascular Risk Factors at Midlife and
the Risk of Dementia and Alzheimer Disease. Arch Neurol
Barrett-Connor E, Edelstein SL, Corey-Bloom J, Wiederholt WC.
Weight loss precedes dementia in community-dwelling older
adults. J Am Geriatr Soc 44:1147-52 (1996).
Hughes TF, Borenstein AR, Schofield E, Wu Y, Larson EB. Asso-
ciation between late-life body mass index and dementia: The Kame
Project. Neurology 72:1741-6 (2009).
Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino
S, Tang MX, et al. Physical Activity, Diet, and Risk of Alzheimer
Disease. JAMA 302:627-37 (2009).
Martin B, Mattson MP, Maudsley S. Caloric restriction and inter-
mittent fasting: Two potential diets for successful brain aging. Age-
ing Res Rev 5:332-53 (2006).
Martin B, Golden E, Egan JM, Mattson MP, Maudsley S. Reduced
energy intake: the secret to a long and healthy life? IBS J Sci 2:35-
Martin B, Golden E, Carlson OD, Egan JM, Mattson MP, Maud-
sley S. Caloric restriction: Impact upon pituitary function and re-
production. Ageing Res Rev 7:209-24 (2008).
Martin B, Ji S, Maudsley S, Mattson MP. "Control" laboratory
rodents are metabolically morbid: Why it matters. Proc Natl Acad
Sci 107:6127-33 (2010).
Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS,
Egan JM, et al. Diet-induced insulin resistance impairs hippocam-
pal synaptic plasticity and cognition in middle-aged rats. Hippo-
campus 18:1085-8 (2008).
Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler
MM. Diabetes mellitus and the risk of dementia: The Rotterdam
Study. Neurology 53:1937-42 (1999).
Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia
and risk of Alzheimer disease. Neurology 63:1187-92 (2004).
Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC.
Increased Risk of Type 2 Diabetes in Alzheimer Disease. Diabetes
Kodl CT, Seaquist ER. Cognitive Dysfunction and Diabetes Melli-
tus. Endocr Rev 29:494-511 (2008).
Cox DJ, Kovatchev BP, Gonder-Frederick LA, Summers KH,
McCall A, Grimm KJ, et al. Relationships Between Hyperglycemia
and Cognitive Performance Among Adults With Type 1 and Type
2 Diabetes. Diabetes Care 28:71-7 (2005).
Cukierman-Yaffe T, Gerstein HC, Williamson JD, Lazar RM,
Lovato L, Miller ME, et al. Relationship Between Baseline Glyce-
mic Control and Cognitive Function in Individuals With Type 2
Diabetes and Other Cardiovascular Risk Factors. Diabetes Care
Biessels GJ, van der Heide LP, Kamal A, Bleys RLAW, Gispen
WH. Ageing and diabetes: implications for brain function. Eur J
Pharm 441:1-14 (2002).
Brownlee M. The Pathobiology of Diabetic Complications. Diabe-
tes 54:1615-25 (2005).
Klein JP, Waxman SG. The brain in diabetes: molecular changes in
neurons and their implications for end-organ damage. Lancet Neu-
rol 2:548-54 (2003).
Ramakrishnan R, Sheeladevi R, Suthanthirarajan N. PKC-[alpha]
mediated alterations of indoleamine contents in diabetic rat brain.
Brain Res Bull 64:189-94 (2004).
Kamal A, Biessels GJ, Urban IJA, Gispen WH. Hippocampal syn-
aptic plasticity in streptozotocin-diabetic rats: impairment of long-
term potentiation and facilitation of long-term depression. Neuro-
science 90:737-45 (1999).
Welsh B, Wecker L. Effects of streptozotocin-induced diabetes on
acetylcholine metabolism in rat brain. Neurochem Res 16:453-60
Biessels GJ, Kappelle AC, Bravenboer B, Erkelens DW, Gispen
WH. Cerebral function in diabetes mellitus. Diabetologia 37:643-
Kim B, Backus C, Oh S, Hayes JM, Feldman EL. Increased Tau
Phosphorylation and Cleavage in Mouse Models of Type 1 and
Type 2 Diabetes. Endocrinology 150:5294-301 (2009).
14 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
 Marks JL, Porte DJ, Stahl WL, Baskin DG. Localization of insulin
receptor mRNA in rat brain by in situ hybridization. Endocrinology
Unger J, McNeill TH, Moxley RT, 3rd, White M, Moss A, Living-
ston JN. Distribution of insulin receptor-like immunoreactivity in
the rat forebrain. Neuroscience 31:143-57 (1989).
Doyle P, Cusin I, Rohner-Jeanrenaud F, Jeanrenaud B. Four-day
hyperinsulinemia in euglycemic conditions alters local cerebral
glucose utilization in specific brain nuclei of freely moving rats.
Brain Res 684:47-55 (1995).
Lucignani G, Namba H, Nehlig A, Porrino LJ, Kennedy C, Sok-
oloff L. Effects of insulin on local cerebral glucose utilization in
the rat. J Cereb Blood Flow Metab 7:309-14 (1987).
Marfaing P, Penicaud L, Broer Y, Mraovitch S, Calando Y, Picon
L. Effects of hyperinsulinemia on local cerebral insulin binding and
glucose utilization in normoglycemic awake rats. Neurosci Lett
Bingham EM, Hopkins D, Smith D, Pernet A, Hallett W, Reed L,
et al. The role of insulin in human brain glucose metabolism: an
18fluoro-deoxyglucose positron emission tomography study. Dia-
betes 51: 3384-90 (2002).
Park CR, Seeley RJ, Craft S, Woods SC. Intracerebroventricular
insulin enhances memory in a passive-avoidance task. Phy Beh
Craft S, Asthana S, Newcomer JW, Wilkinson CW, Matos IT,
Baker LD, et al. Enhancement of Memory in Alzheimer Disease
With Insulin and Somatostatin, but Not Glucose. Arch Gen Psy-
chiatry 56:1135-40 (1999).
Fehm HL, Perras B, Smolnik R, Kern W, Born J. Manipulating
neuropeptidergic pathways in humans: a novel approach to neuro-
pharmacology? Eur J Pharmacol 405:43-54 (2000).
Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich
J, Laufer S, et al. Brain insulin and insulin receptors in aging and
sporadic Alzheimer's disease. J Neural Trans 105:423-38 (1998).
Craft S, Stennis Watson G. Insulin and neurodegenerative disease:
shared and specific mechanisms. The Lancet Neurology 3:169-78
Waugh J, Keating GM, Plosker GL, Easthope S, Robinson DM.
Pioglitazone: a review of its use in type 2 diabetes mellitus. Drugs
Daynes RA, Jones DC. Emerging roles of PPARS in inflammation
and immunity. Nat Rev Immunol 2:748-59 (2002).
Landreth G, Jiang Q, Mandrekar S, Heneka M. PPARgamma ago-
nists as therapeutics for the treatment of Alzheimer's disease. Neu-
rotherapeutics 5:481-9 (2008).
Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, et al. Ibupro-
fen suppresses plaque pathology and inflammation in a mouse
model for Alzheimer's disease. J Neurosci 20:5709-14 (2000).
Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA.
Peroxisome proliferator-activated receptors alpha and gamma are
activated by indomethacin and other non-steroidal anti-
inflammatory drugs. J Biol Chem 272:3406-10 (1997).
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewa-
chter I, Kuiperi C, et al. Acute treatment with the PPARgamma
agonist pioglitazone and ibuprofen reduces glial inflammation and
Abeta1-42 levels in APPV717I transgenic mice. Brain 128:1442-53
Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S,
Haynatzki GR. Rosiglitazone attenuates learning and memory defi-
cits in Tg2576 Alzheimer mice. Exp Neurol 199:265-73 (2006).
Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley
IM, et al. Efficacy of rosiglitazone in a genetically defined popula-
tion with mild-to-moderate Alzheimer's disease. Pharmacogenom-
ics J 6:246-54 (2006).
Du J, Zhang L, Liu S, Zhang C, Huang X, Li J, et al. PPARgamma
transcriptionally regulates the expression of insulin-degrading en-
zyme in primary neurons. Biochem Biophys Res Commun
Kalinin S, Richardson JC, Feinstein DL. A PPARdelta agonist
reduces amyloid burden and brain inflammation in a transgenic
mouse model of Alzheimer's disease. Curr Alzheimer Res 6:431-7
 Schwartz MW, Woods SC, Porte D, Jr., Seeley RJ, Baskin DG.
Central nervous system control of food intake. Nature 404:661-71
Harvey J. Leptin: a diverse regulator of neuronal function. J Neuro-
chem 100:307-13 (2007).
Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL.
Leptin reverses insulin resistance and diabetes mellitus in mice
with congenital lipodystrophy. Nature 401:73-6 (1999).
Jéquier E. Leptin signaling, adiposity, and energy balance. Ann N
Y Acad Sci 967:379-88 (2002).
Power DA, Noel J, Collins R, O'Neill D. Circulating leptin levels
and weight loss in Alzheimer's disease patients. Dement Geriatr
Cogn Disord 12:167-70 (2001).
Olsson T, Nasman B, Rasmuson S, Ahren B. Dual relation between
leptin and cortisol in humans is disturbed in Alzheimer's disease.
Biol Psychiatry 44:374-6 (1998).
Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, et al.
Association of plasma leptin levels with incident Alzheimer disease
and MRI measures of brain aging. JAMA 302:2565-72 (2009).
Doherty GH, Oldreive C, Harvey J. Neuroprotective actions of
leptin on central and peripheral neurons in vitro. Neuroscience
Shanley LJ, Irving AJ, Harvey J. Leptin Enhances NMDA Recep-
tor Function and Modulates Hippocampal Synaptic Plasticity. J
Neurosci 21:RC186- (2001).
Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impair-
ment of long-term potentiation and spatial memory in leptin recep-
tor-deficient rodents. Neuroscience 113:607-15 (2002).
Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol 4:1-
Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD,
Tezapsidis N. Obesity-related leptin regulates Alzheimer's Abeta.
FASEB J 18:1870-8 (2004).
Greco SJ, Sarkar S, Casadesus G, Zhu X, Smith MA, Ashford JW,
et al. Leptin inhibits glycogen synthase kinase-3[beta] to prevent
tau phosphorylation in neuronal cells. Neuroscience Letters
Greco SJ, Sarkar S, Johnston JM, Tezapsidis N. Leptin regulates
tau phosphorylation and amyloid through AMPK in neuronal cells.
Biochem Biophys Res Commun 380:98-104 (2009).
Greco SJ, Sarkar S, Johnston JM, Zhu X, Su B, Casadesus G, et al.
Leptin reduces Alzheimer's disease-related tau phosphorylation in
neuronal cells. Biochem Biophys Res Commun 376:536-41 (2008).
Farr SA, Banks WA, Morley JE. Effects of leptin on memory proc-
essing. Peptides 27:1420-5 (2006).
Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Ashford JW, et
al. Leptin reduces pathology and improves memory in a transgenic
mouse model of Alzheimer's disease. J Alzheimers Dis 19: 1155-67
Harvey J, Solovyova N, Irving A. Leptin and its role in hippocam-
pal synaptic plasticity. Prog Lipid Res 45:369-78 (2006).
De Vriese C, Delporte C. Influence of ghrelin on food intake and
energy homeostasis. Curr Opin Clin Nutr Metab Care 10: 615-9
Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, et
al. Ghrelin controls hippocampal spine synapse density and mem-
ory performance. Nat Neurosci 9:381-8 (2006).
Hou Z, Miao Y, Gao L, Pan H, Zhu S. Ghrelin-containing neuron
in cerebral cortex and hypothalamus linked with the DVC of brain-
stem in rat. Regul Pept 134:126-31 (2006).
Carlini VP, Monzon ME, Varas MM, Cragnolini AB, Schioth HB,
Scimonelli TN, et al. Ghrelin increases anxiety-like behavior and
memory retention in rats. Biochem Biophys Res Commun 299:739-
Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli
TN, de Barioglio SR. Differential role of the hippocampus,
amygdala, and dorsal raphe nucleus in regulating feeding, memory,
and anxiety-like behavioral responses to ghrelin. Biochem Biophys
Res Commun 313:635-41 (2004).
Pedrosa C, Oliveira B, Albuquerque I, Simoes-Pereira C, Vaz-de-
Almeida M, Correia F. Obesity and metabolic syndrome in 7-9
years-old Portuguese schoolchildren. Diabetology & Metabolic
Syndrome 2:40 (2010).
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 15
 Tesauro M, Schinzari F, Caramanti M, Lauro R, Cardillo C. Car-
diovascular and metabolic effects of ghrelin. Curr Diabetes Rev
Gahete MD, Rubio A, Córdoba-Chacón J, Gracia-Navarro F,
Kineman RD, Avila J, et al. Expression of the Ghrelin and Neuro-
tensin Systems is Altered in the Temporal Lobe of Alzheimer's
Disease Patients. Journal of Alzheimer's Disease 22:819-28 (2010).
Atcha Z, Chen WS, Ong AB, Wong FK, Neo A, Browne ER, et al.
Cognitive enhancing effects of ghrelin receptor agonists. Psycho-
pharmacology (Berl) 206:415-27 (2009).
Giordano V, Peluso G, Iannuccelli M, Benatti P, Nicolai R, Calvani
M. Systemic and brain metabolic dysfunction as a new paradigm
for approaching Alzheimer's dementia. Neurochem Res 32:555-67
Cong WN, Golden E, Pantaleo N, White CM, Maudsley S, Martin
B. Ghrelin receptor signaling: a promising therapeutic target for
metabolic syndrome and cognitive dysfunction. CNS Neurol Dis-
ord Drug Targets 9:557-63 (2010).
Dridi S, Taouis M. Adiponectin and energy homeostasis: consensus
and controversy. J Nutr Biochem 20:831-9 (2009).
Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J,
et al. Disruption of adiponectin causes insulin resistance and neoin-
timal formation. J Biol Chem 277:25863-6 (2002).
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et
al. The fat-derived hormone adiponectin reverses insulin resistance
associated with both lipoatrophy and obesity. Nat Med 7:941-6
Ukkola O, Santaniemi M. Adiponectin: a link between excess
adiposity and associated comorbidities? Journal of Molecular
Medicine 80:696-702 (2002).
Diez JJ, Iglesias P. The role of the novel adipocyte-derived hor-
mone adiponectin in human disease. Eur J Endocrinol 148:293-300
Renaldi O, Pramono B, Sinorita H, Purnomo LB, Asdie RH, Asdie
AH. Hypoadiponectinemia: a risk factor for metabolic syndrome.
Acta Med Indones 41:20-4 (2009).
Kroner Z. The relationship between Alzheimer's disease and diabe-
tes: Type 3 diabetes? Altern Med Rev 14:373-9 (2009).
Alim I, Fry WM, Walsh MH, Ferguson AV. Actions of adiponectin
on the excitability of subfornical organ neurons are altered by food
deprivation. Brain Res 1330:72-82 (2010).
Kos K, Harte AL, da Silva NF, Tonchev A, Chaldakov G, James S,
et al. Adiponectin and resistin in human cerebrospinal fluid and
expression of adiponectin receptors in the human hypothalamus. J
Clin Endocrinol Metab 92:1129-36 (2007).
Spranger J, Verma S, Gohring I, Bobbert T, Seifert J, Sindler AL,
et al. Adiponectin does not cross the blood-brain barrier but modi-
fies cytokine expression of brain endothelial cells. Diabetes
Une K, Takei YA, Tomita N, Asamura T, Ohrui T, Furukawa K, et
al. Adiponectin in plasma and cerebrospinal fluid in MCI and Alz-
heimer's disease. Eur J Neurol 2010:18 (2010).
Hüll M, Strauss S, Berger M, Volk B, Bauer J. The participation of
interleukin-6, a stress-inducible cytokine, in the pathogenesis of
Alzheimer's disease. Behav Brain Res 78:37-41 (1996).
Rösler N, Wichart I, Jellinger KA. Clinical significance of neuro-
biochemical profiles in the lumbar cerebrospinal fluid of Alz-
heimer's disease patients. J Neural Transm 108:231-46 (2001).
Nedvídková J, Smitka K, Kopsk? V, Hainer V. Adiponectin, an
adipocyte-derived protein. Physiol Res 54:133-40 (2005).
Gallwitz B. Glucagon-like peptide-1-based therapies for the treat-
ment of type 2 diabetes mellitus. Treat Endocrinol 4:361-70 (2005).
Biswas SC, Buteau J, Greene LA. Glucagon-like peptide-1 (GLP-
1) diminishes neuronal degeneration and death caused by NGF
deprivation by suppressing Bim induction. Neurochem Res
Chapter MC, White CM, DeRidder A, Chadwick W, Martin B,
Maudsley S. Chemical modification of class II G protein-coupled
receptor ligands: frontiers in the development of peptide analogs as
neuroendocrine pharmacological therapies. Pharmacol Ther
Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, et
al. GLP-1 receptor stimulation reduces amyloid-beta peptide accu-
mulation and cytotoxicity in cellular and animal models of Alz-
heimer's disease. J Alzheimers Dis 19:1205-19 (2010).
Perry T, Greig NH. The glucagon-like peptides: a new genre in
therapeutic targets for intervention in Alzheimer's disease. J Alz-
heimers Dis 4:487-96 (2002).
Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan
JM, et al. Glucagon-like peptide-1 decreases endogenous amyloid-
beta peptide (Abeta) levels and protects hippocampal neurons from
death induced by Abeta and iron. J Neurosci Res 72:603-12 (2003).
Perry T, Greig NH. Enhancing central nervous system endogenous
GLP-1 receptor pathways for intervention in Alzheimer's disease.
Curr Alzheimer Res 2:377-85 (2005).
Abbas T, Faivre E, Holscher C. Impairment of synaptic plasticity
and memory formation in GLP-1 receptor KO mice: Interaction be-
tween type 2 diabetes and Alzheimer's disease. Behav Brain Res
McClean PL, Gault VA, Harriott P, Holscher C. Glucagon-like
peptide-1 analogues enhance synaptic plasticity in the brain: a link
between diabetes and Alzheimer's disease. Eur J Pharmacol
Kim B-J, Zhou J, Martin B, Carlson OD, Maudsley S, Greig NH, et
al. Transferrin Fusion Technology: A Novel Approach to Prolong-
ing Biological Half-Life of Insulinotropic Peptides. Journal of
Pharmacology and Experimental Therapeutics 334:682-92 (2010).
D'Amico M, Di Filippo C, Marfella R, Abbatecola AM, Ferraraccio
F, Rossi F, et al. Long-term inhibition of dipeptidyl peptidase-4 in
Alzheimer's prone mice. Exp Gerontol 45:202-7 (2010).
Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal devel-
opment and function. Annu Rev Neurosci 24:677-736 (2001).
Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW,
Bora SH, et al. Brain-derived neurotrophic factor-deficient mice
develop aggressiveness and hyperphagia in conjunction with brain
serotonergic abnormalities. Proc Natl Acad Sci U S A 96:15239-44
Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R, et al. Condi-
tional deletion of brain-derived neurotrophic factor in the postnatal
brain leads to obesity and hyperactivity. Mol Endocrinol 15:1748-
Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J,
Sivaramakrishnan S, et al. A de novo mutation affecting human
TrkB associated with severe obesity and developmental delay. Nat
Neurosci 7:1187-9 (2004).
Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA,
Winslow JW. BDNF mRNA is decreased in the hippocampus of
individuals with Alzheimer's disease. Neuron 7:695-702 (1991).
Murer MG, Yan Q, Raisman-Vozari R. Brain-derived neurotrophic
factor in the control human brain, and in Alzheimer's disease and
Parkinson's disease. Prog Neurobiol 63:71-124 (2001).
Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S. New insights
into brain BDNF function in normal aging and Alzheimer disease.
Brain Res Rev 59:201-20 (2008).
Murer MG, Boissiere F, Yan Q, Hunot S, Villares J, Faucheux B, et
al. An immunohistochemical study of the distribution of brain-
derived neurotrophic factor in the adult human brain, with particu-
lar reference to Alzheimer's disease. Neuroscience 88:1015-32
Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R,
Behlke J, et al. Neuronal sorting protein-related receptor
sorLA/LR11 regulates processing of the amyloid precursor protein.
Proc Natl Acad Sci U S A 102:13461-6 (2005).
Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI,
et al. The lipoprotein receptor LR11 regulates amyloid beta produc-
tion and amyloid precursor protein traffic in endosomal compart-
ments. J Neurosci 26:1596-603 (2006).
Rohe M, Synowitz M, Glass R, Paul SM, Nykjaer A, Willnow TE.
Brain-derived neurotrophic factor reduces amyloidogenic process-
ing through control of SORLA gene expression. J Neurosci
Golden E, Emiliano A, Maudsley S, Windham BG, Carlson OD,
Egan JM, et al. Circulating brain-derived neurotrophic factor and
indices of metabolic and cardiovascular health: data from the Bal-
timore Longitudinal Study of Aging. PLoS One 5:e10099 (2010).
16 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
 Landles C, Bates GP. Huntingtin and the molecular pathogenesis of
Huntington's disease. Fourth in molecular medicine review series.
EMBO Rep 5:958-63 (2004).
Walker FO. Huntington's disease. Lancet 369:218-28 (2007).
Wojaczynska-Stanek K, Adamek D, Marszal E, Hoffman-
Zacharska D. Huntington disease in a 9-year-old boy: clinical
course and neuropathologic examination. J Child Neurol 21:1068-
Macdonald V, Halliday GM, Trent RJ, McCusker EA. Significant
loss of pyramidal neurons in the angular gyrus of patients with
Huntington's disease. Neuropathol Appl Neurobiol 23:492-5
MacDonald ME, Ambrose CM, Duyao MP, Myers RH, Lin C,
Srinidhi L, et al. A novel gene containing a trinucleotide repeat that
is expanded and unstable on Huntington's disease chromosomes.
The Huntington's Disease Collaborative Research Group. Cell
Zuccato C, Belyaev N, Conforti P, Ooi L, Tartari M, Papadimou E,
et al. Widespread disruption of repressor element-1 silencing tran-
scription factor/neuron-restrictive silencer factor occupancy at its
target genes in Huntington's disease. J Neurosci 27:6972-83 (2007).
DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, et
al. Huntingtin is a cytoplasmic protein associated with vesicles in
human and rat brain neurons. Neuron 14:1075-81 (1995).
Leavitt BR, van Raamsdonk JM, Shehadeh J, Fernandes H, Mur-
phy Z, Graham RK, et al. Wild-type huntingtin protects neurons
from excitotoxicity. J Neurochem 96:1121-9 (2006).
Velier J, Kim M, Schwarz C, Kim TW, Sapp E, Chase K, et al.
Wild-type and mutant huntingtins function in vesicle trafficking in
the secretory and endocytic pathways. Exp Neurol 152:34-40
Wellington CL, Leavitt BR, Hayden MR. Huntington disease: new
insights on the role of huntingtin cleavage. J Neural Transm
Cha JH. Transcriptional dysregulation in Huntington's disease.
Trends Neurosci 23:387-92 (2000).
Hickey MA, Chesselet MF. Apoptosis in Huntington's disease.
Prog Neuropsychopharmacol Biol Psychiatry 27:255-65 (2003).
Panov AV, Burke JR, Strittmatter WJ, Greenamyre JT. In vitro
effects of polyglutamine tracts on Ca2+-dependent depolarization of
rat and human mitochondria: relevance to Huntington's disease.
Arch Biochem Biophys 410:1-6 (2003).
Charrin BC, Saudou F, Humbert S. Axonal transport failure in
neurodegenerative disorders: the case of Huntington's disease.
Pathol Biol (Paris) 53:189-92 (2005).
Ferrer I, Goutan E, Marin C, Rey MJ, Ribalta T. Brain-derived
neurotrophic factor in Huntington disease. Brain Res 866:257-61
Zuccato C, Cattaneo E. Role of brain-derived neurotrophic factor in
Huntington's disease. Prog Neurobiol 81:294-330 (2007).
Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D,
Conti L, et al. Loss of huntingtin-mediated BDNF gene transcrip-
tion in Huntington's disease. Science 293:493-8 (2001).
Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, et
al. Huntingtin interacts with REST/NRSF to modulate the tran-
scription of NRSE-controlled neuronal genes. Nat Genet 35:76-83
Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre JP, Ran-
gone H, Cordelieres FP, et al. Huntingtin controls neurotrophic
support and survival of neurons by enhancing BDNF vesicular
transport along microtubules. Cell 118:127-38 (2004).
Björkqvist M, Fex M, Renström E, Wierup N, Petersén A, Gil J, et
al. The R6/2 transgenic mouse model of Huntington's disease de-
velops diabetes due to deficient beta-cell mass and exocytosis.
Hum Mol Genet 14:565-74 (2005).
Sanberg PR, Fibiger HC, Mark RF. Body weight and dietary fac-
tors in Huntington's disease patients compared with matched con-
trols. Med J Aust 1:407-9 (1981).
Farrer LA, Meaney FJ. An anthropometric assessment of
Huntington's disease patients and families. Am J Phys Anthropol
Djousse L, Knowlton B, Cupples LA, Marder K, Shoulson I, Myers
RH. Weight loss in early stage of Huntington's disease. Neurology
 Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, Perin L, et
al. Early energy deficit in Huntington disease: identification of a
plasma biomarker traceable during disease progression. PLoS One
Morales LM, Estevez J, Suarez H, Villalobos R, Chacin de Bonilla
L, Bonilla E. Nutritional evaluation of Huntington disease patients.
Am J Clin Nutr 50:145-50 (1989).
Trejo A, Tarrats RM, Alonso ME, Boll MC, Ochoa A, Velasquez
L. Assessment of the nutrition status of patients with Huntington's
disease. Nutrition 20:192-6 (2004).
Pratley RE, Salbe AD, Ravussin E, Caviness JN. Higher sedentary
energy expenditure in patients with Huntington's disease. Ann Neu-
rol 47:64-70 (2000).
Stoy N, McKay E. Weight loss in Huntington's disease. Ann Neu-
rol 48:130-1 (2000).
Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, Boozer
CN. Energy balance in early-stage Huntington disease. Am J Clin
Nutr 81:1335-41 (2005).
Marder K, Zhao H, Eberly S, Tanner CM, Oakes D, Shoulson I.
Dietary intake in adults at risk for Huntington disease: analysis of
PHAROS research participants. Neurology 73:385-92 (2009).
Fain JN, Del Mar NA, Meade CA, Reiner A, Goldowitz D. Ab-
normalities in the functioning of adipocytes from R6/2 mice that
are transgenic for the Huntington's disease mutation. Hum Mol
Genet 10:145-52 (2001).
Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF,
Lazarowski ER, et al. Thermoregulatory and metabolic defects in
Huntington's disease transgenic mice implicate PGC-1alpha in
Huntington's disease neurodegeneration. Cell Metab 4:349-62
Andreassen OA, Dedeoglu A, Stanojevic V, Hughes DB, Browne
SE, Leech CA, et al. Huntington's disease of the endocrine pan-
creas: insulin deficiency and diabetes mellitus due to impaired in-
sulin gene expression. Neurobiol Dis 11:410-24 (2002).
Hurlbert MS, Zhou W, Wasmeier C, Kaddis FG, Hutton JC, Freed
CR. Mice transgenic for an expanded CAG repeat in the
Huntington's disease gene develop diabetes. Diabetes 48:649-51
Luthi-Carter R, Hanson SA, Strand AD, Bergstrom DA, Chun W,
Peters NL, et al. Dysregulation of gene expression in the R6/2
model of polyglutamine disease: parallel changes in muscle and
brain. Hum Mol Genet 11:1911-26 (2002).
Strand AD, Aragaki AK, Shaw D, Bird T, Holton J, Turner C, et al.
Gene expression in Huntington's disease skeletal muscle: a poten-
tial biomarker. Hum Mol Genet 14:1863-76 (2005).
Popovic V, Svetel M, Djurovic M, Petrovic S, Doknic M, Pekic S,
et al. Circulating and cerebrospinal fluid ghrelin and leptin: poten-
tial role in altered body weight in Huntington's disease. Eur J En-
docrinol 151:451-5 (2004).
Podolsky S, Leopold NA. Abnormal glucose tolerance and arginine
tolerance tests in Huntington's disease. Gerontology 23:55-63
Podolsky S, Leopold NA, Sax DS. Increased frequency of diabetes
mellitus in patients with Huntington's chorea. Lancet 1:1356-8
Lalic NM, Maric J, Svetel M, Jotic A, Stefanova E, Lalic K, et al.
Glucose homeostasis in Huntington disease: abnormalities in insu-
lin sensitivity and early-phase insulin secretion. Arch Neurol
Hunt MJ, Morton AJ. Atypical diabetes associated with inclusion
formation in the R6/2 mouse model of Huntington's disease is not
improved by treatment with hypoglycaemic agents. Exp Brain Res
Martin B, Golden E, Keselman A, Stone M, Mattson MP, Egan JM,
et al. Therapeutic perspectives for the treatment of Huntington's
disease: treating the whole body. Histol Histopathol 23:237-50
Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin
signaling is required for inhibition of glucose production. Nat Med
Lees AJ, Hardy J, Revesz T. Parkinson's disease. Lancet 373:2055-
Pollanen MS, Dickson DW, Bergeron C. Pathology and biology of
the Lewy body. J Neuropathol Exp Neurol 52:183-91 (1993).
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 17
 Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R,
Goedert M. Alpha-synuclein in Lewy bodies. Nature 388:839-40
Mezey E, Dehejia AM, Harta G, Suchy SF, Nussbaum RL, Brown-
stein MJ, et al. Alpha synuclein is present in Lewy bodies in spo-
radic Parkinson's disease. Molecular Psychiatry 3:493-9 (1998).
Kohno R, Sawada H, Kawamoto Y, Uemura K, Shibasaki H, Shi-
mohama S. BDNF is induced by wild-type alpha-synuclein but not
by the two mutants, A30P or A53T, in glioma cell line. Biochem
Biophys Res Commun 318:113-8 (2004).
Baquet ZC, Bickford PC, Jones KR. Brain-derived neurotrophic
factor is required for the establishment of the proper number of do-
paminergic neurons in the substantia nigra pars compacta. J Neuro-
sci 25:6251-9 (2005).
Abbott RA, Cox M, Markus H, Tomkins A. Diet, body size and
micronutrient status in Parkinson's disease. Eur J Clin Nutr 46:879-
Beyer PL, Palarino MY, Michalek D, Busenbark K, Koller WC.
Weight change and body composition in patients with Parkinson's
disease. J Am Diet Assoc 95:979-83 (1995).
Chen H, Zhang SM, Hernan MA, Willett WC, Ascherio A. Weight
loss in Parkinson's disease. Ann Neurol 53:676-9 (2003).
Delikanaki-Skaribas E, Trail M, Wong WW, Lai EC. Daily energy
expenditure, physical activity, and weight loss in Parkinson's dis-
ease patients. Mov Disord 24:667-71 (2009).
Levi S, Cox M, Lugon M, Hodkinson M, Tomkins A. Increased
energy expenditure in Parkinson's disease. BMJ 301:1256-7 (1990).
Markus HS, Cox M, Tomkins AM. Raised resting energy expendi-
ture in Parkinson's disease and its relationship to muscle rigidity.
Clin Sci (Lond) 83:199-204 (1992).
Toth MJ, Fishman PS, Poehlman ET. Free-living daily energy
expenditure in patients with Parkinson's disease. Neurology 48:88-
Chen H, Zhang SM, Schwarzschild MA, Hernan MA, Willett WC,
Ascherio A. Obesity and the risk of Parkinson's disease. Am J Epi-
demiol 159:547-55 (2004).
Logroscino G, Sesso HD, Paffenbarger RS, Jr., Lee IM. Body mass
index and risk of Parkinson's disease: a prospective cohort study.
Am J Epidemiol 166:1186-90 (2007).
Evidente VG, Caviness JN, Adler CH, Gwinn-Hardy KA, Pratley
RE. Serum leptin concentrations and satiety in Parkinson's disease
patients with and without weight loss. Mov Disord 16:924-7
 Lorefalt B, Toss G, Granerus AK. Weight loss, body fat mass, and
leptin in Parkinson's disease. Mov Disord 24:885-90 (2009).
Fiszer U, Michalowska M, Baranowska B, Wolinska-Witort E,
Jeske W, Jethon M, et al. Leptin and ghrelin concentrations and
weight loss in Parkinson's disease. Acta Neurol Scand 121:230-6
Andrews ZB, Erion D, Beiler R, Liu ZW, Abizaid A, Zigman J, et
al. Ghrelin promotes and protects nigrostriatal dopamine function
via a UCP2-dependent mitochondrial mechanism. J Neurosci
Sandyk R. The relationship between diabetes mellitus and Parkin-
son's disease. Int J Neurosci 69:125-30 (1993).
Lipman IJ, Boykin ME, Flora RE. Glucose intolerance in Parkin-
son's disease. J Chronic Dis 27:573-9 (1974).
Becker C, Brobert GP, Johansson S, Jick SS, Meier CR. Diabetes
in patients with idiopathic Parkinson's disease. Diabetes Care
Moroo I, Yamada T, Makino H, Tooyama I, McGeer PL, McGeer
EG, et al. Loss of insulin receptor immunoreactivity from the sub-
stantia nigra pars compacta neurons in Parkinson's disease. Acta
Neuropathol 87:343-8 (1994).
Figlewicz DP, Evans SB, Murphy J, Hoen M, Baskin DG. Expres-
sion of receptors for insulin and leptin in the ventral tegmental
area/substantia nigra (VTA/SN) of the rat. Brain Res 964:107-15
Figlewicz DP, Brot MD, McCall AL, Szot P. Diabetes causes dif-
ferential changes in CNS noradrenergic and dopaminergic neurons
in the rat: a molecular study. Brain Res 736:54-60 (1996).
Morris JK, Zhang H, Gupte AA, Bomhoff GL, Stanford JA, Geiger
PC. Measures of striatal insulin resistance in a 6-hydroxydopamine
model of Parkinson's disease. Brain Res 1240:185-95 (2008).
Baquer NZ, Taha A, Kumar P, McLean P, Cowsik SM, Kale RK, et
al. A metabolic and functional overview of brain aging linked to
neurological disorders. Biogerontology 10:377-413 (2009).
Martin B, Brenneman R, Golden E, Walent T, Becker KG, Prabhu
VV, et al. Growth factor signals in neural cells: coherent patterns
of interaction control multiple levels of molecular and phenotypic
responses. J Biol Chem 284:2493-511 (2009).
St George-Hyslop PH. Molecular genetics of Alzheimer's disease.
Biol Psychiatry 47:183-99 (2000).
Gasser T. Update on the genetics of Parkinson's disease. Mov Dis-
ord 22 Suppl 17:S343-50 (2007).
Received: February 07, 2011 Revised: July 17, 2011 Accepted: August 09, 2011