Alzheimer's Disease In Diabetic Patients Research Articles

Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer's Disease.

As a chronic metabolic disease, diabetes mellitus (DM) is broadly characterized by elevated levels of blood glucose. Novel epidemiological studies demonstrate that some diabetic patients have an increased risk of developing dementia compared with healthy individuals. Alzheimer's disease (AD) is the most frequent cause of dementia and leads to major progressive deficits in memory and cognitive function. Multiple studies have identified an increased risk for AD in some diabetic populations, but it is still unclear which diabetic patients will develop dementia and which biological characteristics can predict cognitive decline. Although few mechanistic metabolic studies have shown clear pathophysiological links between DM and AD, there are several plausible ways this may occur. Since AD has many characteristics in common with impaired insulin signaling pathways, AD can be regarded as a metabolic disease. We conclude from the published literature that the body's diabetic status under certain circumstances such as metabolic abnormalities can increase the incidence of AD by affecting glucose transport to the brain and reducing glucose metabolism. Furthermore, due to its plentiful lipid content and high energy requirement, the brain's metabolism places great demands on mitochondria. Thus, the brain may be more susceptible to oxidative damage than the rest of the body. Emerging evidence suggests that both oxidative stress and mitochondrial dysfunction are related to amyloid-β (Aβ) pathology. Protein changes in the unfolded protein response or endoplasmic reticulum stress can regulate Aβ production and are closely associated with tau protein pathology. Altogether, metabolic disorders including glucose/lipid metabolism, oxidative stress, mitochondrial dysfunction, and protein changes caused by DM are associated with an impaired insulin signal pathway. These metabolic factors could increase the prevalence of AD in diabetic patients via the promotion of Aβ pathology.

The Brain-Heart Axis: Alzheimer's, Diabetes, and Hypertension.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder affecting millions worldwide. Currently, there are only four approved treatments for AD, which improve symptoms modestly. AD is believed to be caused by the formation of intercellular plaques and intracellular tangles in the brain, but thus far all new drugs which target these pathologies have failed clinical trials. New research highlights the link between AD and Type II Diabetes (T2D), and some believe that AD is actually a brain specific form of it termed Type III Diabetes (T3D). Drugs which are currently approved for the treatment of T2D, such as metformin, have shown promising results in improving cognitive function and even preventing the development of AD in diabetic patients. Recent studies shed light on the relationship between the brain and cardiovascular system in which the brain and heart communicate with one another via the vasculature to regulate fluid and nutrient homeostasis. This line of research reveals how the brain-heart axis regulates hypertension and diabetes, both of which can impact cognitive function. In this review we survey past and ongoing research and clinical trials for AD, and argue that AD is a complex and systemic disorder which requires comprehensive approaches beyond the brain for effective prevention and/or treatment.

Neurometabolic Evidence Supporting the Hypothesis of Increased Incidence of Type 3 Diabetes Mellitus in the 21st Century.

The most recent evidence supports the existence of a link between type 2 diabetes (T2DM) and Alzheimer's Disease (AD), described by the new term: type 3 diabetes (T3D). The increasing incidence of T2DM in the 21st century and accompanying reports on the higher risk of AD in diabetic patients prompts the search for pathways linking glycemia disturbances and neurodegeneration. It is suggested that hyperglycemia may lead to glutamate-induced excitotoxicity, a pathological process resulting from excessive depolarization of membrane and uncontrolled calcium ion influx into neuronal cells. On the other hand, it has been confirmed that peripheral insulin resistance triggers insulin resistance in the brain, which may consequently contribute to AD by amyloid beta accumulation, tau phosphorylation, oxidative stress, advanced glycation end products, and apoptosis. Some literature sources suggest significant amylin involvement in additional amyloid formation in the central nervous system, especially under hyperamylinemic conditions. It is particularly important to provide early diagnostics in people with metabolic disturbances, especially including fasting insulin and HOMA-IR, which are necessary to reveal insulin resistance. The present review reveals the most recent and important evidence associated with the phenomenon of T3D and discusses the potential lacks of prevention and diagnostics for diabetes which might result in neurometabolic disorders, from a pharmacotherapy perspective.

High Glucose Promotes Aβ Production by Inhibiting APP Degradation

Abnormal deposition of neuriticplaques is the uniqueneuropathological hallmark of Alzheimer’s disease (AD).Amyloid β protein (Aβ), the major component of plaques, is generated from sequential cleavage of amyloidβ precursor protein (APP) by β-secretase and γ-secretase complex. Patients with diabetes mellitus (DM), characterized by chronic hyperglycemia,have increased risk of AD development.However, the role of high blood glucose in APP processing and Aβ generation remains elusive. In this study, we investigated the effect of high glucose on APP metabolism and Aβ generation in cultured human cells. We found that high glucose treatment significantly increased APP protein level in both neuronal-like and non-neuronal cells, and promoted Aβ generation. Furthermore, we found that high glucose-induced increase of APP level was not due to enhancement of APP gene transcription but resulted from inhibition of APP protein degradation. Taken together, our data indicated that hyperglycemia could promote AD pathogenesis by inhibiting APP degradation and enhancing Aβ production. More importantly, the elevation of APP level and Aβ generation by high glucose was caused by reduction of APP turnover rate.Thus,our study provides a molecular mechanism of increased risk of developing AD in patients withDMand suggests thatglycemic control might be potentially beneficial for reducing the incidence of AD in diabetic patients and delaying the AD progression.

PPARγ-mediated advanced glycation end products regulation of neural stem cells

Hyperglycemia is accompanied by an accelerated rate of advanced glycation end products (AGEs) formation, which is found to be associated with the pathogenesis of diabetic cognitive deficit, including Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in controlling the proliferation of neural stem cells (NSCs) and their neuronal differentiation. We investigate the hypothesis that PPARγ could mediate AGEs-related regulation of NSCs, by which AGEs possibly fulfill important roles in diabetic-related cognitive impairment. We found that AGEs down-regulated the proliferation and neurogenic differentiation of NSCs, and protein level of PPARγ. PPARγ agonist reversed the proliferation through the aid of AGE-BSA, with the exclusion of the neuronal differentiation of the NSCs which were also downregulated by AGE-BSA. These findings extend our understanding of the central role of PPARγ in AGEs-related neurogenesis impairment, which probably increased risks of cognitive deficits or AD in diabetic patients.

Diagnostic utility of serum or cerebrospinal fluid levels of toxic advanced glycation end-products (TAGE) in early detection of Alzheimer’s disease

Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques and neurofibrillary tangles (NFTs), the major constituents of which are amyloid beta protein (A beta) and tau protein, respectively. Based on the disease pathology, numerous blood and cerebrospinal fluid (CSF) tests have been proposed for early detection of AD. However, there is no definite clinical method to determine in which patients with mild cognitive impairment will progress to AD with dementia. Therefore, to develop a novel promising biomarker for early diagnosis of AD is urgently needed. Several epidemiological studies have reported moderately increased risks for AD in diabetic patients compared with general population. In diabetes mellitus, the formation and accumulation of advanced glycation end-products (AGEs), senescent macroprotein derivatives, progress more rapidly. In addition, recent understanding of this process has confirmed that AGEs-their receptor (RAGE) interactions may play a role in the pathogenesis of neurodegenerative disorders including AD. In human AD brains, AGEs are distributed in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. In this paper, we discuss the pathophysiological role for toxic AGEs (TAGE) in AD. We further review here the possibility that serum or cerebrospinal fluid levels of TAGE could become a promising biomarker for early detection of AD.

Serum or cerebrospinal fluid levels of glyceraldehyde-derived advanced glycation end products (AGEs) may be a promising biomarker for early detection of Alzheimer’s disease

Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques and neurofibrillary tangles (NFTs), the major constituents of which are the amyloid beta protein (Abeta) and tau protein, respectively. Several epidemiological studies have reported moderately increased risks of AD in diabetic patients compared with general population. In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. Recent understandings of this process have confirmed that AGEs - their receptor (RAGE) interactions may play a role in the pathogenesis of diabetic vascular complications and neurodegenerative disorders including AD. Indeed, it has been demonstrated that AGEs can be identified immunohistochemically to be present in both senile plaques and NFTs from patients with AD. Glycation of Abeta markedly enhances its aggregation in vitro, and the glycation of tau, in addition to hyperphosphorylation, appears to enhance the formation of paired helical filaments. Further, RAGE has been found a specific cell surface receptor for Abeta peptite, thus eliciting neuronal cell perturbation. The active participation of RAGE in the pathogenesis of AD has also been confirmed in RAGE-overexpressed transgenic mice. Moreover, we have recently found that glyceraldehyde-derived AGEs, one of the representative ligands for RAGE, exerted cytopathic effects on cultured neuronal cells and that neurotoxic effect of diabetic serum was completely blocked by neutralizing antibodies against glyceraldehydes-derived AGEs. These observations led us to hypothesize that serum or cerebrospinal fluid (CSF) levels of glyceraldehyde-derived AGEs could become a promising biomarker for early detection of AD. We also would like to propose the possible ways of testing our hypothesis. Are the concentrations of glyceraldehyde-derived AGEs in serum or CSF elevated early in the course of dementia? Are these levels correlated with disease severity and progression, especially in patients with diabetes? These clinical studies clarify whether use of serum or CSF levels of glyceraldehyde-derived AGEs as a biomarker for AD might enable more effective diagnosis and treatment of patients with this devastating disorder.