Modern societies face the increasing burden of age-related diseases, in particular Alzheimer’s disease (AD) and type 2 diabetes (T2D). There is some evidence that the causes underlying both diseases are linked. Do AD and T2D represent the endpoint of aged, exhausted, and dysfunctional cells having reached their maximal life expectancy or are AD and T2D the consequences of living in superabundance including excessive food supply, work demands, psychosocial stress, and an excessive sedentary life style?
In a special issue of the Journal of Alzheimer’s Disease (April 2009), nineteen contributions examine the possible connections between AD and T2D.
Numerous epidemiological studies have described the incidence of both AD and T2D in the Western world and extensively defined common environmental risk factors. Guest Editors Angelika Bierhaus and Peter P. Nawroth, both of the University of Heidelberg, have assembled a group of prominent investigators to explore the connections between AD and T2D pathologies using literature reviews of current human studies, overviews of animal models, reviews of basic pathophysiology findings, and biochemical analyses.
In the introduction Bierhaus and Nawroth note that several pathological features have been identified as common denominators of AD and T2D including impaired glucose/energy metabolism, altered insulin-signaling pathways, mitochondrial dysfunction, oxidative stress, and inflammation.
Daniel Kopf and Lutz Frölich report a systematic review of fourteen studies that examined the risk of incident Alzheimer’s disease in diabetic patients. All studies reported risk ratios greater than one with four studies showing statistically significant excess risk.
Pablo Toro, Peter Schönknecht, and Johannes Schröder follow with the results of a study of almost 200 subjects born between 1930 and 1932. For those with either mild cognitive impairment (MCI) or with AD, there was an increased tendency for T2D.
José A. Luchsinger and Deborah R. Gustafson present a comprehensive review of the epidemiologic evidence linking the continuum of adiposity and T2D with AD. The mechanisms relating adiposity and T2D to AD may include hyperinsulinemia, advanced products of glycosylation, cerebrovascular disease, and products of adipose tissue metabolism. 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 also present a unique opportunity for prevention and treatment of AD.
Ceramides are a type of lipid molecule that are both neurotoxic and causes insulin resistance. Ming Tong and Suzanne M. de la Monte report on their investigation of the role of ceramides as mediators of neurodegeneration using an in vitro culture model. Exposure to two different ceramides impaired energy metabolism, viability, and insulin and insulin-like growth factor signaling mechanisms, and resulted in increased levels of AβPP-Aβ and pTau, while an inactive ceramide analogue had no significant effect on these parameters.
Following this line of investigation, Lascelles E. Lyn-Cook, Jr., Margot Lawton, Ming Tong, Elizabeth Silbermann, Lisa Longato, Ping Jiao, Princess Mark, Jack R. Wands, Haiyan Xu and Suzanne M. de la Monte used pairs of mice fed a high-fat diet (HFD) or a normal diet and found that mild neurodegeneration and brain insulin resistance resulted from the high-fat diet. They found that ceramide production increased in the HFD mice and that obesity, T2D and nonalcoholic steatohepatitis (NASH) might all be mediated by the excess ceramides.
In the area of possible therapies for AD, 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, and Sraboni Sarkar write about a possible use of leptin to reduce the affects of AD. They speculate that a deficiency in leptin levels or function may contribute to systemic and central nervous system abnormalities leading to AD.
Three articles focus on the role of oxidative stresses and the development of AD. Paula I. Moreira, Ana I. Duarte, Maria S. Santos, A. Cristina Rego, and Catarina R. Oliveira write about the processes underlying the pathogenesis of Alzheimer’s disease, including impaired glucose/energy metabolism, mitochondrial dysfunction, oxidative stress and altered insulin-signaling pathways. V. Prakash Reddy, Xiongwei Zhu, George Perry, and Mark A. Smith discuss how oxidative stress plays a major role in diabetes as well as in Alzheimer’s disease and other related neurological diseases. 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. Sajjad Muhammad, Angelika Bierhaus, and Markus Schwaninger review 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.
Allan Jones, Philipp Kulozik, Anke Ostertag, and Stephan Herzig review common metabolic and inflammatory processes implicated in the pathogenesis of both T2D and AD. In particular, they emphasize the role of critical transcriptional checkpoints in the control of cellular metabolism, insulin sensitivity, and inflammation. These transcriptional regulators might hold great promise as new therapeutic targets in the potentially combined treatment of type 2 diabetes and Alzheimer’s disease. Other inflammatory processes might be involved in both AD and T2D. Ivica Granic, Amalia M. Dolga, Ingrid M. Nijholt, Gertjan van Dijk, and Ulrich L. M. Eisel investigate how both inflammation and the inducible nuclear factor NF-κB might be involved in both diabetes mellitus and Alzheimer's disease. Clement T. Loy and Stephen M. Twigg discuss how advanced glycation end products (AGEs) and growth factor dysregulation may link diabetes and AD.
Receptor for Advanced Glycation Endproducts (RAGE) is a superfamily of cell molecules which serves as a receptor for amyloid-β peptide (Aβ). 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. Shi Du Yan, Angelika Bierhaus, Peter P. Nawroth, and David M. Stern suggest that RAGE may be a therapeutic target for AD.
Masayoshi Takeuchi and Sho-ichi Yamagishi contribute a study of Toxic Advanced Glycation End-products (TAGE). These AGEs can cause oxidative stress in numerous types of cells, which could contribute to the pathological changes of diabetic vascular complications and AD. Akihiko Taguchi discusses how RAGE-mediated chronic inflammation can initiate a degenerative positive feedback loop between endothelium and neuronal cells. Elzbieta Kojro and Rolf Postina explore how RAGE and Amyloid-beta protein precursor (AβPP) proteolysis can be affected by insulin and how proteolysis of RAGE may prevent transport of Aβ across the blood-brain barrier.
A contributing factor to oxidative stress can be excess free iron. Sandro Altamura and Martina U. Muckenthaler review experimental evidences for an involvement of iron in Alzheimer’s disease and Parkinson’s disease. They also propose a role for iron in atherosclerosis, another frequent disorder of aging.
Michael Morcos and Harald Hutter report that the classical model organism in aging research, the nematode Caenorhabditis elegans (C. elegans), shares many similarities at the molecular level to pathological processes found in humans. 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.
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