Mechanisms Associated with Type 2 Diabetes as a Risk Factor for Alzheimer-Related Pathology

Men Su, Kambiz Naderi, Nathalie Samson, Ihsen Youssef, Livia Fülöp, Zsolt Bozso, Serge Laroche, Benoit Delatour, Sabrina Davis

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4 Citations (Scopus)

Abstract

Current evidence suggests dementia and pathology in Alzheimer’s Disease (AD) are both dependent and independent of amyloid processing and can be induced by multiple ‘hits’ on vital neuronal functions. Type 2 diabetes (T2D) poses the most important risk factor for developing AD after ageing and dysfunctional IR/PI3K/Akt signalling is a major contributor in both diseases. We developed a model of T2D, coupling subdiabetogenic doses of streptozotocin (STZ) with a human junk food (HJF) diet to more closely mimic the human condition. Over 35 weeks, this induced classic signs of T2D (hyperglycemia and insulin dysfunction) and a modest, but stable deficit in spatial recognition memory, with very little long-term modification of proteins in or associated with IR/PI3K/Akt signalling in CA1 of the hippocampus. Intracerebroventricular infusion of soluble amyloid beta 42 (Aβ42) to mimic the early preclinical rise in Aβ alone induced a more severe, but short-lasting deficits in memory and deregulation of proteins. Infusion of Aβ on the T2D phenotype exacerbated and prolonged the memory deficits over approximately 4 months, and induced more severe aberrant regulation of proteins associated with autophagy, inflammation and glucose uptake from the periphery. A mild form of environmental enrichment transiently rescued memory deficits and could reverse the regulation of some, but not all protein changes. Together, these data identify mechanisms by which T2D could create a modest dysfunctional neuronal milieu via multiple and parallel inputs that permits the development of pathological events identified in AD and memory deficits when Aβ levels are transiently effective in the brain.

Original languageEnglish
Pages (from-to)5815-5834
Number of pages20
JournalMolecular Neurobiology
Volume56
Issue number8
DOIs
Publication statusPublished - Aug 15 2019

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Keywords

  • Alzheimer’s disease
  • Amyloid beta
  • CA1
  • Environment enrichment
  • Human junk food
  • Insulin
  • Object recognition
  • PI3K-Akt signalling
  • Type 2 diabetes

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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