Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus)

Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 3.61). 01/2007; 10(4):417-22.
Source: PubMed

ABSTRACT Recent studies from our laboratories and others suggest that calorie restriction (CR) may benefit Alzheimer's disease (AD) by preventing amyloid-beta (Abeta) neuropathology in the mouse models of AD. Moreover, we found that promotion of the NAD+-dependent SIRT1 mediated deacetylase activity, a key regulator in CR extension of life span, may be a mechanism by which CR influences AD-type neuropathology. In this study we continued to explore the role of CR in AD-type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). Monkeys were maintained on the normal and CR diets throughout the entire lifespan until they died of natural causes. We found that 30% CR resulted in reduced contents of Abeta1-40 and Abeta1-42 peptides in the temporal cortex of Squirrel monkeys, relative to control (CON) fed monkeys. The decreased contents of cortical Abeta peptide inversely correlated with SIRT1 protein concentrations in the same brain region; no detectable change in total full-length amyloid-beta protein precursor (AbetaPP) level was found. Most interestingly, we found that 30% CR resulted in a select elevation of alpha- but not beta- or gamma- secretase activity which coincided with decreased ROCK1 protein content in the same brain region, relative to CON group. Collectively, the study suggests that investigation of the role of CR in non-human primates may provide a valuable approach for further clarifying the role of CR in AD.

1 Follower
  • Source
    • "The protective effect of SIRT1 against AD was initially observed in CR studies, where CR reduced Aβ and plaque generation in the brains of transgenic AD mice (Patel et al., 2005; Wang et al., 2005a). Similarly, the reduction of Aβ was also noticed in the cortex of fasted squirrel monkeys and is inversely correlated with SIRT1 levels (Qin et al., 2006a). These studies imply that SIRT1 is involved in neuroprotection against AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Brain aging is characterized by progressive loss of neurophysiological functions that is often accompanied by age-associated neurodegeneration. Calorie restriction has been linked to extension of lifespan and reduction of the risk of neurodegenerative diseases in experimental model systems. Several signaling pathways have been indicated to underlie the beneficial effects of calorie restriction, among which the sirtuin family has been suggested to play a central role. In mammals, it has been established that sirtuins regulate physiological responses to metabolism and stress, two key factors that affect the process of aging. Sirtuins represent a promising new class of conserved deacetylases that play an important role in regulating metabolism and aging. This review focuses on current understanding of the relation between metabolic pathways involving sirtuins and the brain aging process, with focus on SIRT1 and SIRT3. Identification of therapeutic agents capable of modulating the expression and/or activity of sirtuins is expected to provide promising strategies for ameliorating neurodegeneration. Future investigations regarding the concerted interplay of the different sirtuins will help us understand more about the aging process, and potentially lead to the development of therapeutic approaches for the treatment of age-related neurodegenerative diseases and promotion of successful aging.
    Frontiers in Aging Neuroscience 07/2013; 5:36. DOI:10.3389/fnagi.2013.00036 · 2.84 Impact Factor
  • Source
    • "The protective effect of SIRT1 against AD was initially observed in caloric restriction studies, where calorie restriction reduced Aβ and plaque generation in the brains of transgenic AD mice (Patel et al., 2005; Wang et al., 2005a). Similarly, the reduction of Aβ is also noticed in the cortex of starved squirrel monkeys and is inversely correlated with SIRT1 levels (Qin et al., 2006a). These studies imply that SIRT1 is involved in the neuroprotection against AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Silent information regulator two proteins (sirtuins or SIRTs) are a group of histone deacetylases whose activities are dependent on and regulated by nicotinamide adenine dinucleotide (NAD(+)). They suppress genome-wide transcription, yet upregulate a select set of proteins related to energy metabolism and pro-survival mechanisms, and therefore play a key role in the longevity effects elicited by calorie restriction. Recently, a neuroprotective effect of sirtuins has been reported for both acute and chronic neurological diseases. The focus of this review is to summarize the latest progress regarding the protective effects of sirtuins, with a focus on SIRT1. We first introduce the distribution of sirtuins in the brain and how their expression and activity are regulated. We then highlight their protective effects against common neurological disorders, such as cerebral ischemia, axonal injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Finally, we analyze the mechanisms underlying sirtuin-mediated neuroprotection, centering on their non-histone substrates such as DNA repair enzymes, protein kinases, transcription factors, and coactivators. Collectively, the information compiled here will serve as a comprehensive reference for the actions of sirtuins in the nervous system to date, and will hopefully help to design further experimental research and expand sirtuins as therapeutic targets in the future.
    Progress in Neurobiology 09/2011; 95(3):373-95. DOI:10.1016/j.pneurobio.2011.09.001 · 10.30 Impact Factor
  • Source
    • "The authors further showed that SIRT1 can deacetylate and coactivate the retinoic acid receptor β, a known modulator of ADAM10 transcription (Donmez et al., 2010). Collectively, the original discovery from Qin et al. (2006a, 2006b) and the confirmatory studies from Donmez et al. (2010) suggest that pharmacological activation of SIRT1 may represent a promising approach to prevent amyloid deposition and neurodegeneration in AD (Wang et al., 2010a, 2010b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resveratrol is a naturally occurring polyphenolic compound associated with beneficial effects on aging, metabolic disorders, inflammation and cancer in animal models and resveratrol is currently being tested in numerous clinical trials. Resveratrol may exert these effects by targeting several key metabolic sensor/effector proteins, such as AMPK, SIRT1, and PGC-1α. Resveratrol has also received considerable attention recently for its potential neuroprotective effects in neurodegenerative disorders where AMPK, SIRT1 or PGC-1α may represent promising therapeutic targets. A recent study published in Experimental Neurology (Ho et al., 2010) examined the therapeutic potential of a micronised proprietary resveratrol formulation, SRT501 in the N171-82Q transgenic mouse model of Huntington's disease (HD). HD is a progressive and devastating genetic neurodegenerative disorder that is associated with downregulation of PGC-1α activity. The Ho et al. study found that SRT501 treatment did not lead to significant improvement in weight loss, motor performance, survival and striatal atrophy. However, other studies have reported neuroprotective effects of resveratrol and a distantly related polyphenol, fisetin, in HD models. HD has been associated with diabetes mellitus. Interestingly, evidence from the Ho et al. study suggests a resveratrol formulation induced beneficial anti-diabetic effect in N171-82Q mice. This commentary summarizes the pertinent outcomes from the Ho et al. study and discusses the further prospects of resveratrol and other polyphenols, including novel grape-derived polyphenols, in the treatment of HD and other neurodegenerative disorders.
    Experimental Neurology 08/2011; 232(1):1-6. DOI:10.1016/j.expneurol.2011.08.014 · 4.62 Impact Factor
Show more