Diabetes and Cholesterol Dyshomeostasis Involve Abnormal α-Synuclein and Amyloid Beta Transport in Neurodegenerative Diseases

The understanding of molecular mechanisms underlying diet and Alzheimer's disease and the cholesterol connection are important for the prevention and treatment of Alzheimer's disease linked to Type 3 diabetes and aberrant lipid metabolism. Cholesterol modulates amyloid beta generation with the ATP-binding cassette transporter 1 as a major regulator of cholesterol and phospholipids from cell membranes that are involved in amyloid beta transport from the brain to the liver for metabolism. In Parkinson's disease, the α-synuclein protein binds to cholesterol (tilted peptide 67-78/isooctyl chain) in cell membranes. Fatty acids and phospholipids such as phosphatidylinositol in membranes sensitive to amyloid beta and α-synuclein binding/aggregation indicate the involvement of lipids in the progression of Alzheimer's disease. Atherogenic diets with abnormal cell cholesterol homeostasis exist as a cellular mechanism, which is common to the aggregation of amyloid beta and α-synuclein proteins that induce both Alzheimer's disease and Parkinson's disease. Sirtuin 1,a nuclear receptor known to regulate cell functions by deacetylating both histone and non-histone targets when down regulated is associated with circadian abnormalities and with poor glucose and cholesterol metabolism linked to abnormal amyloid beta metabolism in Alzheimer's disease and increased α-synuclein aggregation in Parkinson's disease. The global obesity and Type 2 diabetes epidemic indicate that the down regulation of Sirtuin 1 with increased inflammatory processes and abnormal immune responses associated with increased plasma α-synuclein levels, has become important for the modulation of membrane ion channels and impairments in protein degradation with abnormal endoplasmic reticulummitochondrial interactions associated with disturbed peripheral amyloid beta metabolism common to both Parkinson's disease and Alzheimer's disease.