Journal of Alzheimer's Disease - Volume 16, issue 4

Authors: Jones, Allan | Kulozik, Philipp | Ostertag, Anke | Herzig, Stephan

Article Type: Research Article

Abstract: Numerous epidemiological and experimental studies have established a strong connection between type 2 diabetes and the risk of the development of Alzheimer's disease. Indeed, several pathological features have been identified as common denominators of diabetic and Alzheimer's patients, including insulin resistance, dyslipidemia and inflammation, suggesting a close connection between the two disorders. Here we review common metabolic and inflammatory processes implicated in the pathogenesis of both disorders. In particular, the role of critical transcriptional checkpoints in the control of cellular metabolism, insulin sensitivity, and inflammation will be emphasized in this context. These transcriptional regulators hold great promise as new therapeutic …targets in the potentially combined treatment of type 2 diabetes and Alzheimer's disease in the future. Show more

Keywords: Alzheimer's disease, energy homeostasis, insulin signaling, metabolic syndrome, transcription, type 2 diabetes

DOI: 10.3233/JAD-2009-0973

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 787-808, 2009

Authors: Granic, Ivica | Dolga, Amalia M. | Nijholt, Ingrid M. | van Dijk, Gertjan | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Inflammatory processes are a hallmark of many chronic diseases including Alzheimer's disease and diabetes mellitus. Fairly recent statistical evidence indicating that type 2 diabetes increases the risk of developing Alzheimer's disease has led to investigations of the potential common processes that could explain this relation. Here, we review the literature on how inflammation and the inducible nuclear factor NF-κB might be involved in both diabetes mellitus and Alzheimer's disease and whether these factors can link both diseases.

Keywords: Alzheimer's disease, inflammation, insulin, insulin-degrading enzyme, nuclear factor-κB, receptor for advanced glycation endproducts (RAGE), tumor necrosis factor, type 2 diabetes mellitus

DOI: 10.3233/JAD-2009-0976

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 809-821, 2009

Authors: Loy, Clement T. | Twigg, Stephen M.

Article Type: Research Article

Abstract: Diabetes mellitus and Alzheimer's disease (AD) each become increasingly common with age. Diabetes causes many chronic end-organ complications and among them is dementia, which may be due to an underlying vascular cause, as well as being related to AD. The pathogenic mechanisms that lead to diabetes complications include advanced glycation end products (AGEs) and growth factor dysregulation. This review explores the evidence for epidemiological links between diabetes and AD, as well as potential pathogenic mechanisms whereby AGEs, their cellular receptors, and key growth factors may contribute to AD development and progression in diabetes. Directions for future research are also discussed.

Keywords: Alzheimer's disease, advanced glycation end products, diabetes mellitus, growth factors

DOI: 10.3233/JAD-2009-0997

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 823-831, 2009

Authors: Yan, Shi Du | Bierhaus, Angelika | Nawroth, Peter P. | Stern, David M.

Article Type: Research Article

Abstract: Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for amyloid-β peptide (Aβ) on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE is observed in regions of the brain affected by Alzheimer's disease (AD), and Aβ-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling mechanisms including the MAP kinase pathway. RAGE-mediated activation of p38 MAP kinase in neurons causes Aβ-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression …of RAGE in an Aβ-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-β protein precursor. Interception of Aβ interaction with RAGE, by infusion of soluble RAGE, decreases Aβ content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Aβ accumulation. These data suggest that RAGE may be a therapeutic target for AD. Show more

Keywords: Amyloid-β peptide receptor, cerebral blood flow, endothelin-1, immunoglobulin superfamily, long-term potentiation, transgenic model

DOI: 10.3233/JAD-2009-1030

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 833-843, 2009

Authors: Takeuchi, Masayoshi | Yamagishi, Sho-ichi

Article Type: Research Article

Abstract: Recent clinical evidence has suggested diabetes mellitus as one of the risk factors for the development and progression of Alzheimer's disease (AD). Continuous hyperglycemia is a causative factor for diabetic vascular complications, and it enhances the generation of advanced glycation end-products (AGEs), thereby being involved in the pathogenesis of AD as well. Moreover, there is a growing body of evidence to show that the interaction of glyceraldehyde-derived AGEs (Glycer-AGE), which is a predominant structure of toxic AGEs (TAGE), with a receptor for AGEs elicits oxidative stress generation in numerous types of cells, all of which could contribute to the pathological …changes of diabetic vascular complications and AD. Indeed, we have recently found that Glycer-AGE induces apoptotic cell death in cultured cortical neuronal cells. We also found that the neurotoxic effect of diabetic serum on neuronal cells was blocked by a neutralizing antibody raised against the Glycer-AGE epitope. Moreover, in human AD brain, Glycer-AGE is distributed in the cytosol of neurons in the hippocampus. These results suggest that Glycer-AGE is involved in the pathogenesis of AD. In this review, we discuss the pathophysiological role for AGEs in the development and progression of diabetic vascular complications and AD, especially focusing on TAGE. Show more

Keywords: Advanced glycation end-products (AGEs), Alzheimer's disease (AD), diabetes mellitus (DM), diabetic vascular complications, glyceraldehyde-derived AGEs (Glycer-AGE), receptor for AGEs (RAGE), toxic AGEs (TAGE)

DOI: 10.3233/JAD-2009-0974

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 845-858, 2009

Authors: Taguchi, Akihiko

Article Type: Research Article

Abstract: The homeostasis of neuronal cells is maintained by the cerebral circulation and blood-brain barrier. In addition to age-related physiological decline, diabetes disturbs microvascular functions through mechanisms, including activation of protein kinase C, excess production of reactive oxygen species and cellular activation of the receptor for advanced glycation endproducts (RAGE). Impaired microvasculature has been correlated with pathological changes in both vascular dementia and Alzheimer's disease. Furthermore, RAGE-mediated chronic inflammation initiates a degenerative positive feedback loop between endothelium and neuronal cells. The levels of circulating CD34+ cells, which support maintenance of the microvasculature and are decreased in diabetes, have been proposed …to provide a marker of the contribution of cerebrovascular factors in patients with cognitive impairment. Show more

Keywords: Cerebral infarction, cerebral microvasculature, receptor for advanced glycation end products (RAGE), vascular dementia

DOI: 10.3233/JAD-2009-0975

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 859-864, 2009

Authors: Kojro, Elzbieta | Postina, Rolf

Article Type: Research Article

Abstract: Epidemiological studies have linked type 2 diabetes mellitus (T2DM) with an increased risk of developing Alzheimer's disease (AD). In T2DM, the elevated blood glucose level promotes formation of advanced glycation end products (AGEs). The receptor for AGEs (RAGE) is a type I membrane-protein and is also able to import amyloid-β (Aβ) from the blood across the blood-brain-barrier into the brain. Oligomeric Aβ peptides disturb synaptic function in the brain and are believed to contribute to the development of AD. Aβ peptides are released from the amyloid-β protein precursor (AβPP) after sequential proteolysis by β- and γ-secretases but α-secretase-mediated cleavage of …AβPP prevents Aβ generation. Insulin influences Aβ production by modulating α-secretase activity and Aβ degradation. Recent publications demonstrate that RAGE is subjected to protein ectodomain shedding. Proteolysis of RAGE occurs constitutively and is inducible by activation of protein kinase C. Alpha-secretase-like enzymes release the ligand binding domain of RAGE from the cell surface and after that γ-secretase processes the membrane-remaining part of RAGE. Proteolysis of RAGE may represent a regulatory mechanism in RAGE signal transduction and in addition may prevent Aβ peptide transport across the blood-brain-barrier. Current data suggest that the sequential proteolysis of RAGE is homologous to AβPP processing. Show more

Keywords: α-secretase cleavage, amyloid-β protein precursor, γ-secretase cleavage, protein shedding, receptor for advanced glycation end products

DOI: 10.3233/JAD-2009-0998

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 865-878, 2009

Authors: Altamura, Sandro | Muckenthaler, Martina U.

Article Type: Research Article

Abstract: Excess free iron generates oxidative stress that hallmarks diseases of aging. The observation that patients with Alzheimer's disease or Parkinson's disease show a dramatic increase in their brain iron content has opened the possibility that disturbances in brain iron homeostasis may contribute to the pathogenesis of these disorders. While the reason for iron accumulation is unknown, iron localization correlates with the production of reactive oxygen species in those areas of the brain that are prone to neurodegeneration. A role for iron is also proposed in atherosclerosis, a further frequent disorder of aging. We will review experimental evidences for an involvement …of iron in these diseases and discuss some mouse models with impairment in iron-related genes that may be useful to study the role of iron in these disorders. Show more

Keywords: Alzheimer's disease, atherosclerosis, diseases of aging, iron, iron homeostasis, mouse model, Parkinson's disease, reactive oxygen species

DOI: 10.3233/JAD-2009-1010

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 879-895, 2009

Authors: Morcos, Michael | Hutter, Harald

Article Type: Research Article

Abstract: Diabetes mellitus, with its complications, and Alzheimer's disease (AD) share many similarities. Both are age-related and associated with enhanced formation of advanced glycation endproducts (AGEs) and oxidative stress, factors that can be observed during the normal aging process as well. AGE deposits can be found in areas of atherosclerotic lesions in diabetes and in senile plaques and neurofibrillary tangles in AD. A classical model organism in aging research is the nematode Caenorhabditis elegans (C. elegans). Though C. elegans lacks a vascular system, it has been introduced in diabetes and AD research since it shares many similarities at the molecular level …to pathological processes found in humans. AGEs accumulate in C. elegans, and increased AGE-formation and mitochondrial AGE-modification are responsible for increased oxidative stress and limiting life span. Moreover, C. elegans has an accessible and well characterized nervous system and features several genes homologous to human genes implicated in AD like amyloid-β protein precursor, presenilins and tau. In addition, human genes linked to AD, such as amyloid-β or tau, can be expressed and studied in C. elegans. So far, C. elegans research has contributed to a better understanding of the function of AD-related genes and the development of this disease. Show more

Keywords: Advanced glycation endproducts, Alzheimer's disease, C. elegans, mitochondria, oxidative stress

DOI: 10.3233/JAD-2009-0977

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 897-908, 2009

Article Type: Discussion

DOI: 10.3233/JAD-2009-1026

Citation: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 909-917, 2009