Volume 16, Number 4, April 2009 - Special Issue "Oxidative Stress, Reactive Metabolites, Inflammation, and RAGE—Building a Bridge from Alzheimer's Disease to Diabetes and Vice Versa" (Guest Editor: Angelika Bierhaus)

Pages 673-675
Angelika Bierhaus and Peter P. Nawroth
Preface: The Alzheimer’s Disease-Diabetes Angle: Inevitable Fate of Aging or Metabolic Imbalance Limiting Successful Aging

Pages 677-685
Daniel Kopf, Lutz Frölich
Risk of Incident Alzheimer’s Disease in Diabetic Patients: A Systematic Review of Prospective Trials
Abstract: Diabetes mellitus is an established risk factor of cognitive decline. This excess risk has frequently been attributed to cerebrovascular disease. The contribution of diabetes mellitus to the risk of Alzheimer’s disease is less clear. We performed a systematic literature review based on prospective studies that examined the risk of incident Alzheimer’s disease in diabetic patients. Fourteen studies in eleven different populations fulfilled the entry criteria. Only one study per population was included by pre-defined criteria, leaving eleven studies for analysis. All studies reported risk ratios greater than one (median 1.59, range 1.15-2.7). In four studies, this excess risk was statistically significant (median 1.73, range 1.59-1.9); in seven studies the lower border of the 95% confidence interval was below 1.0. Factors associated with significant results were a sample size of 600 or more diabetic subjects, inclusion of patients with mild glycemic dysregulation as assessed by oral glucose tolerance test, and a high proportion of diagnoses of Alzheimer’s disease verified by autopsy or magnetic resonance imaging. Diabetes mellitus is likely to increase the risk of Alzheimer’s disease. The association of Alzheimer’s disease and diabetes mellitus is more clear-cut, if mild cases of diabetes mellitus are included in the analysis.

Pages 687-691
Pablo Toro, Peter Schönknecht, Johannes Schröder
Type II Diabetes in Mild Cognitive Impairment and Alzheimer’s Disease: Results from a Prospective Population-Based Study in Germany
Abstract: Diabetes mellitus type 2 (T2DM) is considered to be an important risk factor for mild cognitive impairment (MCI) and subsequent Alzheimer’s disease (AD). The majority of studies relating T2DM to MCI and AD were performed in North America. We investigated the potential impact of T2DM on the development of MCI and AD in the Interdisciplinary Longitudinal Study on Adult Development and Aging which involves a representative birth cohort of subjects born between 1930 and 1932 in Germany. Subjects received a thorough psycho-geriatric examination and neuropsychological testing; particular care was taken to exclude subjects with severe medical or neurological conditions sufficient to explain the cognitive deficits, or other major psychiatric disorders. When compared to healthy subjects (n=159), patients with MCI (n=108) or AD (n=26) showed a tendency towards increased prevalence rates for T2DM (16% vs. 23%; χ2=1.7, p = 0.18). In both patients with MCI and controls, T2DM was associated with psychomotor slowing but not deficits in other cognitive domains typically involved in MCI. Our findings indicate that T2DM is involved in MCI and may aggravate the clinical picture as a concomitant factor.

Pages 693-704
José A. Luchsinger, Deborah R. Gustafson
Adiposity, Type 2 Diabetes, and Alzheimer’s Disease
Abstract: This manuscript provides a comprehensive review of the epidemiologic evidence linking the continuum of adiposity and type 2 diabetes (T2D) with Alzheimer’s disease (AD). The mechanisms relating adiposity and T2D to AD may include hyperinsulinemia, advanced products of glycosylation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of AD but the data on this association in old age is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of AD. Hyperinsulinemia is a risk factor for T2D, and numerous studies have shown a relation of T2D with higher AD risk. The implication of these associations is that a large proportion of the world population may be at increased risk of AD given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and T2D. However these associations may present a unique opportunity for prevention and treatment of AD. Several studies in the prevention and treatment of T2D are currently conducting, or have planned, cognition ancillary studies. In addition, clinical trials using insulin sensitizers in the treatment or prevention of AD are under way.

Pages 705-714
Ming Tong, Suzanne M. de la Monte
Mechanisms of Ceramide-Mediated Neurodegeneration
Abstract: Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can be associated with cognitive impairment or early neurodegeneration. Previously, we showed that diet-induced obesity with T2DM and NASH results in mild neurodegeneration with some features of AD, including brain insulin resistance. In a companion study, we correlated obesity/T2DM/NASH-associated central nervous system (CNS) abnormalities with increased pro-ceramide gene expression in liver. Since ceramides are neurotoxic and cause insulin resistance, we directly investigated the role of ceramides as mediators of neurodegeneration using an in vitro culture model. We treated PNET2 human CNS neuronal cells with D-erythro-Ceramide analogs (C2Cer:N-acetylsphinganine and C6Cer: N-hexanoylsphinganine), or the inactive dihydroceramide analog (C2DCer) for 48 h, and probed for changes in genes and proteins that are critical to insulin/IGF signaling, and associated with neurodegeneration. Exposure to C6Cer > C2Cer impaired energy metabolism, viability, and insulin and insulin-like growth factor signaling mechanisms, and resulted in increased levels of AβPP-Aβ and pTau, whereas C2D had no significant effect on these parameters. CNS exposure to neurotoxic ceramides from exogenous sources, including liver, can cause neurodegeneration with impairments in insulin and IGF signaling mechanisms, similar to the findings in experimental models of obesity/T2DM, and NASH.

Pages 715-729
Lascelles E. Lyn-Cook Jr., Margot Lawton, Ming Tong, Elizabeth Silbermann, Lisa Longato, Ping Jiao, Princess Mark, Jack R. Wands, Haiyan Xu, Suzanne M. de la Monte
Hepatic Ceramide May Mediate Brain Insulin Resistance and Neurodegeneration in Type 2 Diabetes and Non-alcoholic Steatohepatitis
Abstract: Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can be complicated by cognitive impairment and neurodegeneration. Experimentally, high fat diet (HFD)-induced obesity with T2DM causes mild neurodegeneration with brain insulin resistance. Since ceramides are neurotoxic, cause insulin resistance, and are increased in T2DM, we investigated the potential role of ceramides as mediators of neurodegeneration in the HFD obesity/T2DM model. We pair-fed C57BL/6 mice with a HFD or control diet for 4-20 weeks and examined pro-ceramide gene expression in liver and brain and neurodegeneration in the temporal lobe. HFD feeding gradually increased body weight, but after 16 weeks, liver weight surged (P<0.001) due to lipid (triglyceride) accumulation (P<0.001), and brain weight declined (P<0.0001-Trend analysis). HFD feeding increased ceramide synthase, serine palmitoyl transferase, and sphingomyelinase expression in liver (P<0.05-P<0.001), but not brain. In HFD fed mice, temporal lobe levels of ubiquitin (P<0.001) and 4-hydroxynonenol (P<0.05 or P<0.01) increased, and tau, β-actin, and choline acetyltransferase levels decreased (P<0.05-P<0.001) with development of NASH. In obesity, T2DM, or NASH, neurodegeneration with brain insulin resistance may be mediated by excess hepatic production of neurotoxic ceramides that readily cross the blood-brain barrier.

Pages 731-740
Nikolaos Tezapsidis, Jane M. Johnston, Mark A. Smith, J. Wesson Ashford, Gemma Casadesus, Nikolaos K. Robakis, Benjamin Wolozin, George Perry, Xiongwei Zhu, Steven J. Greco, Sraboni Sarkar
Leptin: A Novel Therapeutic Strategy for Alzheimer's Disease
Abstract: Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer’s disease (AD) at the molecular and physiological level. One activity of leptin is the control of AMP-dependent kinase (AMPK). In addition to maintaining lipid levels, AMPK regulates glycogen synthase kinase-3, which modulates tau phosphorylation. Leptin has been shown to reduce the amount of extracellular amyloid-β, both in cell culture and animal models of AD, as well as reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models of AD. In humans, weight loss often precedes the onset of dementia in AD and the level of circulating leptin is inversely proportional to the severity of dementia among AD patients. It is speculated that a deficiency in leptin levels or function may contribute to systemic and central nervous system abnormalities leading to AD, suggesting that a leptin replacement therapy may be beneficial for AD. This may be an attractive alternative to the drugs that are currently under development.

Pages 741-761
Paula I. Moreira, Ana I. Duarte, Maria S. Santos, A. Cristina Rego, Catarina R. Oliveira
An Integrative View of the Role of Oxidative Stress, Mitochondria and Insulin in Alzheimer’s Disease
The processes underlying the pathogenesis of Alzheimer’s disease involve several factors including impaired glucose/energy metabolism, mitochondrial dysfunction, oxidative stress and altered insulin-signaling pathways. This review is mainly devoted to discuss evidence supporting the notion that mitochondrial dysfunction and oxidative stress are interconnected and intimately associated with the development and progression of Alzheimer’s disease. Furthermore, the review explores the role of insulin signaling in the pathophysiology of the disease. Indeed, several studies have begun to find links between insulin and mechanisms with clear pathogenic implications for this disorder. Understanding the key mechanisms involved in the etiopathogenesis of Alzheimer’s disease may provide opportunities for the design of efficacious preventive and therapeutic strategies.

Pages 763-774
V. Prakash Reddy, Xiongwei Zhu, George Perry, Mark A. Smith (Handling Editor: Ralph N. Martins)
Oxidative Stress in Diabetes and Alzheimer’s Disease
Abstract: Oxidative stress plays a major role in diabetes as well as in Alzheimer’s disease and other related neurological diseases. Intracellular oxidative stress arises due to the imbalance in the production of reactive oxygen/reactive nitrogen species and cellular antioxidant defense mechanisms. In turn, the excess reactive oxygen/reactive nitrogen species mediate the damage of proteins and nucleic acids, which have been shown to have direct and deleterious consequences in diabetes and Alzheimer’s disease. Oxidative stress also contributes to the production of advanced glycation end products through glycoxidation and lipid peroxidation. The advanced glycation end products and lipid peroxidation products are ubiquitous to diabetes and Alzheimer’s disease and serve as markers of disease progression in both disorders. Antioxidants and advanced glycation end products inhibitors, either induced endogenously or exogenously introduced, may counteract with the deleterious effects of the reactive oxygen/reactive nitrogen species and thereby, in prevention or treatment paradigms, attenuate or substantially delay the onset of these devastating pathologies.

Pages 775-785
Sajjad Muhammad, Angelika Bierhaus, Markus Schwaninger
Reactive Oxygen Species in Diabetes-induced Vascular Damage, Stroke, and Alzheimer’s Disease
Abstract: A morphological hallmark of Alzheimer’s disease (AD) is the deposition of amyloid-β peptide in plaques and along blood vessels. As several lines of evidence suggest that vascular dysfunction contributes to AD, the pathophysiology of diabetic vasculopathy and stroke may cast light on the vascular component of AD. In this review, we compile some recent findings on the role of reactive oxygen species in diabetes-induced vascular dysfunction and the consequent cerebral ischemia and compare them with key findings in AD. Overall, there is compelling evidence that reactive oxygen species play a key role in the pathophysiology of AD. Unfortunately, this insight has not yet led to a new treatment of AD.

Pages 787-808
Allan Jones, Philipp Kulozik, Anke Ostertag, Stephan Herzig
Common Pathological Processes and Transcriptional Pathways in Alzheimer’s Disease and Type 2 Diabetes
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.

Pages 809-821
Ivica Granic, Amalia M. Dolga, Ingrid M. Nijholt, Gertjan van Dijk, Ulrich L.M. Eisel
Inflammation and NF-κB in Alzheimer's Disease and Diabetes
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 investigation 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.

Pages 823-831
Clement T. Loy, Stephen M. Twigg
Growth Factors, AGEing, and the Diabetes Link in Alzheimer’s Disease
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.

Pages 833-843
Shi Du Yan, Angelika Bierhaus, Peter P. Nawroth, David M. Stern
RAGE and Alzheimer’s Disease: A Progression Factor for Amyloid-β-Induced Cellular Perturbation?
Abstract: Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell 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 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.

Pages 845-858
Masayoshi Takeuchi, Sho-ichi Yamagishi
Involvement of Toxic AGEs (TAGE) in the Pathogenesis of Diabetic Vascular Complications and Alzheimer’s Disease
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.

Pages 859-864
Akihiko Taguchi
Vascular Factors in Diabetes and Alzheimer’s Disease
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.

Pages 865-878
Elzbieta Kojro, Rolf Postina
Regulated Proteolysis of RAGE and AβPP as Possible Link Between Type 2 Diabetes Mellitus and Alzheimer’s Disease
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 Aβgeneration. 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.

Pages 879-895
Sandro Altamura and Martina U. Muckenthaler
Iron Toxicity in Diseases of Aging: Alzheimer’s Disease, Parkinson’s Disease and Atherosclerosis
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.

Pages 897-908
Michael Morcos, Harald Hutter
The Model Caenorhabditis elegans in Diabetes Mellitus and Alzheimer’s Disease
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 limited 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.

Pages 909-917
Transcript of Live Discussion held at the Alzheimer Research Forum
Alzheimer Research Forum Live Discussion: Calcium in AD Pathogenesis