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.

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

“…The multiple reasons for cerebral glucose hypometabolism in AD, its relationship with oxidative stress and the use of alternative substrates under such condition have been well reviewed [43,44]. The metabolic implications of AD pathogenesis in the context of brain insulin deficiency and insulin resistance have been extensively discussed in several recent publications [45,46]. Although multiple causes have been attributed to altered food intake and loss of body weight in AD, the fact also implies a role of hormones like insulin and adipokines in its pathogenesis [48,49,50].…”

“…It has been envisaged that Alzheimer's disease may be a type of 'brain diabetes' or 'type 3 diabetes' resulting from both insulin deficiency and insulin resistance in the brain [46,84,101]. This is supported by a body of evidence such as the decreased level of insulin, insulin mRNA and insulin receptor protein in brain, de-sensitization of insulin receptor and decreased levels and impaired functioning of downstream components of insulin signaling pathway in AD brain [46,103,104,105,106,107].…”

Bone-brain crosstalk and potential associated diseases

“…First, leptin regulates appetite, energy expenditure and fertility by signaling in the brain [33,36,34,[42][43][44][45]. Second, leptin does not appear during evolution linked to any aspect of energy metabolism or reproduction, but is instead associated with bone (re)modeling.…”

Chronic nicotine attenuates behavioral and synaptic plasticity impairments in a streptozotocin model of Alzheimer’s disease

“…Dysfunctional insulin signaling in the brain triggers the sporadic type of Alzheimer's disease (sAD) (de la Monte and Tong, 2014), which is characterized by decreased brain glucose metabolism (Hoyer, 1998;Fro¨lich et al, 1998;Watson and Craft, 2003). Disturbances in central insulin signaling have also been shown to affect amyloid-beta (Ab) levels and tau protein hyperphosphorylation (Hoyer, 2004;Salkovic-Petrisic et al, 2009), supporting the notion that sAD may be considered to be the brain type of diabetes (Hoyerm 2002;.…”