When Aging-Onset Diabetes Is Coming Across With Alzheimer Disease: Comparable Pathogenesis And Therapy.
Department of Laboratory Medicine & Pathology, Kogod Center on Aging, Mayo Clinic,200 First Street SW, Rochester, Minnesota 55905,USA. Experimental gerontology
(Impact Factor: 3.49).
05/2013; 48(8). DOI: 10.1016/j.exger.2013.04.013
Diabetes Mellitus is a metabolic disorder that is characterized by high blood glucose because of the insulin-resistance and insulin-deficiency in Type 2,while the insulin deficiency due to destruction of islet cells in the pancreas in Type 1 . The development of type 2 diabetes is caused by a combination of lifestyle and genetic factors. Aging patients with diabetes are at increased risk of developing cognitive and memory dysfunctions,which is one of the significant symptoms of Alzheimer Disease(AD). Also, over 2/3 of AD patients were clinically indentified with impairment of glucose. Cognitive dysfunction would be associated with poor self-care ability in diabetes patients.This review will briefly summarize the current knowledge of the pathogenesis of these two diseases and highlight similarities in their pathophysiologies .Furthermore, we will shortly discuss recent progress in the insulin-targeted strategy, aiming to explore the inner linkage between these two diseases in aging populations.
Available from: Atanu Biswas
- "blocking the genesis and progression of sporadic AD, but the results are still not unequivocal in this respect   . "
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ABSTRACT: Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.
Available from: Daphne Atlas
- "Aging patients with Type 2 diabetes (T2D) are at a high risk of developing cognitive and memory impairments including some of Alzheimer disease 0 s (AD) most significant symptoms . In recent years it has become evident that some characteristics of AD are regulated by insulin-like growth factor signaling cascades . "
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ABSTRACT: Diabetes is a high risk factor for dementia and has been shown in transgenic animals to cause a potentiation of indices that are pre-symptomatic of Alzheimer's disease. To further elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes, we monitored the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brain of male leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rats and human neuroblastoma SH-5HY5 cells. Daily i.p injection of CB3 to ZDF rats inhibited the phosphorylation of the MAP kinases, c-jun NH2-terminal kinase (JNK) and p38 MAP kinases (p38MAPK), and prevented the expression of thioredoxin-interacting-protein (TXNIP/TBP-2) in ZDF rat brain. Although plasma glucose/insulin remained high, CB3 also increased the phosphorylation of AMP-ribose activating kinase (AMPK) and inhibited p70S6K kinase in the brain. Both CB3 and CB4 reversed apoptosis induced by inhibiting thioredoxin reductase as monitored by decreasing caspase 3 cleavage and PARP dissociation in SH-SY5Y cells. The decrease in JNK and p38MAPK activity in the absence of a change in plasma glucose implies a decrease in oxidative or inflammatory stress in the ZDF rat brain. CB3 not only attenuated MAPK phosphorylation and activated AMPK in the brain, but it also diminished apoptotic markers, most likely acting via the MAPK-AMPK-mTOR pathway. These results were correlated with CB3 and CB4 inhibiting inflammation progression and protection from oxidative stress induced apoptosis in human neuronal cells. We suggest that Trx1 mimetic peptides could become beneficial for preventing neurological disorders associated with diabetes.
Available from: Noé Alvarado-Vásquez
- "The diversity of factors previously proposed (Aβ, glucose, insulin, etc.) as the origin of AD makes it difficult to find the central mechanisms that cause the disease (Baptista et al., 2013; Boudina et al., 2007; Liu et al., 2006; Russell et al., 2002). However, an increasing number of works support the role of hyperglycemia as a risk factor for the development of neuronal damage (Tomlinson and Gardiner, 2008) and starting point of Alzheimer disease (Tang et al., 2013). Nevertheless, it is still an issue of strong debate how a high glucose concentration could favor brain damage in the presence or absence of Aβ in individuals at risk of developing AD. "
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ABSTRACT: Diabetes mellitus (DM) is considered a risk factor for the development of Alzheimer disease (AD); however, how DM favors evolution of AD is still insufficiently understood. Hyperglycemia in DM is associated to an increase in mitochondrial reactive oxygen species (ROS) generation, as well as damage of hippocampal cells, reflected by changes in morphological and mitochondrial functionality. Similar mitochondrial damage has been observed when amyloid beta (Aβ) accumulates in the brain of AD patients. In DM, the excess of glucose in the brain induces higher activity of the hexosamine biosynthesis pathway (HBP), it synthesizes UDP-N-acetylglucosamine (UDP-GlcNAc), which is used by O-linked N-acetylglucosamine transferase (OGT) to catalyze O-GlcNAcylation of numerous proteins. Although O-GlcNAcylation plays an important role in maintaining structure and cellular functionality, chronic activity of this pathway has been associated with insulin resistance and hyperglycemia-induced glucose toxicity. Three different forms of OGT are known: nucleocytoplasmic (ncOGT), short (sOGT), and mitochondrial (mOGT). Previous reports showed that overexpression of ncOGT is not toxic to the cell; in contrast, overexpression of mOGT is associated with cellular apoptosis. In this work, we suggest that hyperglycemia in the diabetic patient could induce greater expression and activity of mOGT, modifying the structure and functionality of mitochondria in hippocampal cells, accelerating neuronal damage, and favoring the start of AD. In consequence, mOGT activity could be a key point for AD development in patients with DM.
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