Abstract
Current hypotheses and theories regarding the pathogenesis of Alzheimer’s disease (AD) heavily implicate brain insulin resistance (IR) as a key factor. Despite the many well-validated metrics for systemic IR, the absence of biomarkers for brain-specific IR represents a translational gap that has hindered its study in living humans. In our lab, we have been working to develop biomarkers that reflect the common mechanisms of brain IR and AD that may be used to follow their engagement by experimental treatments. We present two promising biomarkers for brain IR in AD: insulin cascade mediators probed in extracellular vesicles (EVs) enriched for neuronal origin, and two-dimensional magnetic resonance spectroscopy (MRS) measures of brain glucose. As further evidence for a fundamental link between brain IR and AD, we provide a novel analysis demonstrating the close spatial correlation between brain expression of genes implicated in IR (using Allen Human Brain Atlas data) and tau and beta-amyloid pathologies. We proceed to propose the bold hypotheses that baseline differences in the metabolic reliance on glycolysis, and the expression of glucose transporters (GLUT) and insulin signaling genes determine the vulnerability of different brain regions to Tau and/or Amyloid beta (Aβ) pathology, and that IR is a critical link between these two pathologies that define AD. Lastly, we provide an overview of ongoing clinical trials that target IR as an angle to treat AD, and suggest how biomarkers may be used to evaluate treatment efficacy and target engagement.
Highlights
We present two promising biomarkers for brain insulin resistance (IR) in Alzheimer’s disease (AD): insulin cascade mediators probed in extracellular vesicles (EVs) enriched for neuronal origin, and two-dimensional magnetic resonance spectroscopy (MRS) measures of brain glucose
As further evidence for a fundamental link between brain IR and AD, we provide a novel analysis demonstrating the close spatial correlation between brain expression of genes implicated in IR and tau and beta-amyloid pathologies
We proceed to propose the bold hypotheses that baseline differences in the metabolic reliance on glycolysis, and the expression of glucose transporters (GLUT) and insulin signaling genes determine the vulnerability of different brain regions to Tau and/or Amyloid beta (Aβ) pathology, and that IR is a critical link between these two pathologies that define AD
Summary
The binding of insulin to the insulin receptor leads to the recruitment and phosphorylation of the insulin receptor substrates 1 and 2 (IRS1 and 2; Draznin, 2006). Persistent activation of the insulin receptor results in excessive phosphorylation of Ser and Thr residues on IRSs (Czech et al, 1988; Singh, 1993; Tanti et al, 1994) This aberrant phosphorylation of IRS results in reduced insulin receptor binding sensitivity and translocation of the active portion of IRS from the membrane to the cytosol, and is one of the main molecular underpinnings of insulin resistance (IR; Aguirre et al, 2002; Boura-Halfon and Zick, 2009; Copps and White, 2012; Ryu et al, 2014). In systemic and organ-specific IR states, the ability of insulin to stimulate glucose uptake via GLUT transporters is impaired, requiring higher than normal concentrations of extracellular insulin to maintain normal glucose uptake to match cellular metabolic needs (Lebovitz, 2001)
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