Diabetes and Alzheimer's Connections Explored

In a special issue of the Journal of Alzheimer's Disease, nineteen contributions examine the possible connections between Alzheimer's disease and type 2 diabetes.

Numerous epidemiological studies have described the incidence of both Alzheimer's and type 2 diabetes in the Western world and extensively deﬁned common environmental risk factors. Guest Editors Angelika Bierhaus and Peter P. Nawroth have assembled a group of prominent investigators to explore the connections between Alzheimer's and type 2 diabetes 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 Alzheimer's and type 2 diabetes including impaired glucose/energy metabolism, altered insulin-signaling pathways, mitochondrial dysfunction, oxidative stress, and inflammation.

Risk of Incident Alzheimer's Disease in Diabetic Patients: A Systematic Review of Prospective Trials.
A systematic review of fourteen studies that examined the risk of incident Alzheimer's in diabetic patients. All studies reported risk ratios greater than one with four studies showing statistically significant excess risk.

Type II Diabetes in Mild Cognitive Impairment and Alzheimer's Disease: Results from a Prospective Population-Based Study in Germany.
A study of almost 200 subjects born between 1930 and 1932. For those with either mild cognitive impairment or with Alzheimer's, there was an increased tendency for type 2 diabetes.

Adiposity, Type 2 Diabetes, and Alzheimer's Disease.
A comprehensive review of the epidemiologic evidence linking the continuum of adiposity and type 2 diabetes with Alzheimer's. The mechanisms relating adiposity and type 2 diabetes to Alzheimer's 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 Alzheimer's given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and type 2 diabetes. However these associations may also present a unique opportunity for prevention and treatment of Alzheimer's.

Mechanisms of Ceramide-Mediated Neurodegeneration.
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.

Hepatic Ceramide May Mediate Brain Insulin Resistance and Neurodegeneration in Type 2 Diabetes and Non-alcoholic Steatohepatitis.
Pairs of mice were fed a high-fat diet or a normal diet and it was 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.

Leptin: A Novel Therapeutic Strategy for Alzheimer's Disease.
The possible use of leptin to reduce the affects of Alzheimer's was explored and it was speculated that a deficiency in leptin levels or function may contribute to systemic and central nervous system abnormalities leading to Alzheimer's.

An Integrative View of the Role of Oxidative Stress, Mitochondria and Insulin in Alzheimer's Disease.
The processes underlying the pathogenesis of Alzheimer's, including impaired glucose/energy metabolism, mitochondrial dysfunction, oxidative stress and altered insulin-signaling pathways.

Oxidative Stress in Diabetes and Alzheimer's Disease.
How oxidative stress plays a major role in diabetes as well as in Alzheimer's and other related neurological diseases. The advanced glycation end products and lipid peroxidation products are ubiquitous to diabetes and Alzheimer's and serve as markers of disease progression in both disorders.

Reactive Oxygen Species in Diabetes-induced Vascular Damage, Stroke, and Alzheimer's Disease.
A review of 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 Alzheimer's.

Common Pathological Processes and Transcriptional Pathways in Alzheimer's Disease and Type 2 Diabetes.
A review of common metabolic and inflammatory processes implicated in the pathogenesis of both type 2 diabetes and Alzheimer's. 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. Other inflammatory processes might be involved in both Alzheimer's and type 2 diabetes.

Inflammation and NF-κB in Alzheimer's Disease and Diabetes.
How both inflammation and the inducible nuclear factor NF-κB might be involved in both diabetes mellitus and Alzheimer's.

Growth Factors, AGEing, and the Diabetes Link in Alzheimer's Disease.
How advanced glycation end products (AGEs) and growth factor dysregulation may link diabetes and Alzheimer's.

RAGE and Alzheimer's Disease: A Progression Factor for Amyloid-β-Induced Cellular Perturbation?
Receptor for Advanced Glycation Endproducts is suggested as a therapeutic target for Alzheimer's. 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, and Aβ-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling.

Involvement of Toxic AGEs (TAGE) in the Pathogenesis of Diabetic Vascular Complications and Alzheimer's Disease.
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 Alzheimer's.

Vascular Factors in Diabetes and Alzheimer's Disease.
How RAGE-mediated chronic inflammation can initiate a degenerative positive feedback loop between endothelium and neuronal cells.

Regulated Proteolysis of RAGE and AβPP as Possible Link Between Type 2 Diabetes Mellitus and Alzheimer's Disease.
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.

Iron Toxicity in Diseases of Aging: Alzheimer's Disease, Parkinson's Disease and Atherosclerosis.
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 and Parkinson's disease. They also propose a role for iron in atherosclerosis, another frequent disorder of aging.

The Model Caenorhabditis elegans in Diabetes Mellitus and Alzheimer's Disease.
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 Alzheimer's like amyloid-β protein precursor, presenilins and tau.

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References:
1. The Journal of Alzheimer's Disease.