Insulin resistance in Alzheimer's disease

Kelly T. Dineley, Jordan B. Jahrling, Larry Denner

Research output: Contribution to journalReview article

54 Scopus citations

Abstract

Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD.Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD.

Original languageEnglish (US)
Pages (from-to)92-103
Number of pages12
JournalNeurobiology of Disease
Volume72
Issue numberPart A
DOIs
StatePublished - Dec 1 2014

    Fingerprint

Keywords

  • Alzheimer's disease
  • Animal models
  • Cognitive function
  • ERK
  • Insulin resistance
  • Learning and memory
  • Metabolism
  • Mitochondria
  • PPAR gamma
  • Therapeutic windows

ASJC Scopus subject areas

  • Neurology

Cite this