Insulin resistance in Alzheimer's disease

Abstract

The links between systemic insulin resistance (IR), brain-specific IR and Alzheimer’s disease (AD) has been an extremely productive area of current research. This review will cover the fundamentals and pathways leading to IR; its connection to AD via cellular mechanisms, the most prominent methods and models used to examine it, an introduction to the role of extracellular vesicles (EVs) as a source of biomarkers for IR and AD, and an overview of modern clinical studies on the subject. To provide additional context, we also present a novel analysis of the spatial correlation of gene expression in the brain with the aid of Allen Human Brain Atlas data. Ultimately, examining the relation between IR and AD can be seen as a means of advancing the understanding of both disease states, with IR being a promising target for therapeutic strategies in AD treatment. In conclusion, we highlight the therapeutic potential of targeting brain IR in AD and the main strategies to pursue this goal.

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

“…From the standpoint of disease pathophysiology, the higher levels seen in AD participants also match the glucose elevation observed in diabetes mellitus,42 potentially due to their common underpinning of brain insulin resistance 43. Besides these earlier MRS findings, a recent human postmortem study also showed a dramatic glucose elevation in all brain regions of the AD specimens examined 44.…”

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

“…Eventually, this signaling culminates in the translocation of insulin-dependent glucose transporter 4 (GLUT4) towards the plasma membrane so that the glucose uptake and energy production could be enhanced. Liver, skeletal muscle and adipose tissue are main targets of insulin action [134, 135]. …”

“…Normally, the activation of the insulin pathway strengthens the degrading process of excessive Aβ and thus effectively avoids the formation of extracellular Aβ plaques. However, when insulin insensitivity occurs in neuronal cells, the functionality of γ-secretase could also be stimulated, which promotes the cleavage of APP into Aβ [142, 143]. Additionally, due to the secondary hyperinsulinemia by insulin non-responsiveness, the expression of insulin-degrading enzyme (IDE) is greatly suppressed, which physiologically functions as a potent scavenger of Aβ in brain cells [144].…”

“…Additionally, due to the secondary hyperinsulinemia by insulin non-responsiveness, the expression of insulin-degrading enzyme (IDE) is greatly suppressed, which physiologically functions as a potent scavenger of Aβ in brain cells [144]. Meanwhile, in vivo evidence has also shown that Aβ could deteriorate insulin resistance by decreasing the density of membrane IRs as well as restricting IRS-1 activity via an inhibitory phosphorylation on its serine residue [143]. This feed-forward loop outlines the vital connection between insulin resistance and Aβ [145].…”

“…Moreover, GSK3 is the main kinase targeting the tau protein, whose aberrant activation significantly promotes phosphorylation on intracellular tau [148]. Meanwhile, insulin resistance has a negative impact on PP2A, which is normally an indispensable tau phosphatase under physiological conditions [143]. These mechanisms jointly explain the potential interplay between insulin resistance and tau protein aggregation, revealing that insulin resistance may be regarded as an important contributor of the pathogenesis of AD (Fig.…”