Brain metabolic dysfunction at the core of Alzheimer's disease

Abstract

Growing evidence supports the concept that Alzheimer's disease (AD) is fundamentally a metabolic disease with molecular and biochemical features that correspond with diabetes mellitus and other peripheral insulin resistance disorders. Brain insulin/IGF resistance and its consequences can readily account for most of the structural and functional abnormalities in AD. However, disease pathogenesis is complicated by the fact that AD can occur as a separate disease process, or arise in association with systemic insulin resistance diseases, including diabetes, obesity, and non-alcoholic fatty liver disease. Whether primary or secondary in origin, brain insulin/IGF resistance initiates a cascade of neurodegeneration that is propagated by metabolic dysfunction, increased oxidative and ER stress, neuro-inflammation, impaired cell survival, and dysregulated lipid metabolism. These injurious processes compromise neuronal and glial functions, reduce neurotransmitter homeostasis, and cause toxic oligomeric pTau and (amyloid beta peptide of amyloid beta precursor protein) AβPP-Aβ fibrils and insoluble aggregates (neurofibrillary tangles and plaques) to accumulate in brain. AD progresses due to: (1) activation of a harmful positive feedback loop that progressively worsens the effects of insulin resistance; and (2) the formation of ROS- and RNS-related lipid, protein, and DNA adducts that permanently damage basic cellular and molecular functions. Epidemiologic data suggest that insulin resistance diseases, including AD, are exposure-related in etiology. Furthermore, experimental and lifestyle trend data suggest chronic low-level nitrosamine exposures are responsible. These concepts offer opportunities to discover and implement new treatments and devise preventive measures to conquer the AD and other insulin resistance disease epidemics.

Keywords: Advanced glycation end-products; Alzheimer's disease; Ceramides; Insulin resistance; Lifestyle; Metabolic syndrome; N-Nitrosodiethylamine; Nitrosamine; Nitrosamines; Non-alcoholic fatty liver disease; Obesity; Reactive nitrogen species; Streptozotocin; Type 3 diabetes.

Fig. 1

Primary and secondary mediators of neurodegeneration are linked to harmful positive feedback loops driven by insulin resistance. Alzheimer’s disease, non-alcoholic steatohepatitis (NASH), polycystic ovarian syndrome (PCO), Type 2 diabetes mellitus, obesity, and metabolic syndrome are all associated with insulin resistance. Once established, insulin resistance drives a positive feedback cycle of inflammation, endoplasmic reticulum (ER) stress, dysregulated lipid metabolism with increased ceramide generation, and metabolic dysfunction in the affected organs and tissues. The consequences are increased cell death, impaired function, and organ/tissue degeneration. With regard to the brain, insulin resistance can occur as a primary disease process leading to selective neurodegeneration (Alzheimer’s disease). Alternatively, neurodegeneration could be consequential to insulin resistance in other organs, and arise in association with NASH, PCO, diabetes, obesity, and metabolic syndrome. We propose that toxic lipids (ceramides) released from injured and dying cells exert neurotoxic effects and cause insulin resistance. In primary AD, toxic ceramides are generated primarily in the brain. With regard to systemic diseases, ceramides made in peripheral organs injure the brain after crossing the blood–brain barrier. A self-reinforcing mal-signaling loop leads to progressive neurodegeneration. However, we are still left with the question of underlying etiologies. Epidemiologic and experimental data point toward chronic low-level nitrosamine exposures through dietary, agricultural, and smoking sources as upstream causes of insulin resistance diseases. Our over-arching hypothesis is that while high levels of nitrosamine exposures cause cancer, chronic low, sub-mutagenic doses cause insulin resistance-associated degenerative diseases. Host factors including aging and lifestyle measures may dictate propensity for different subtypes of insulin resistance diseases, including Alzheimer’s.