Depletion of caveolin-1 in type 2 diabetes model induces alzheimer's disease pathology precursors

Jacqueline A. Bonds, Aashutosh Shetti, Abdullah Bheri, Zhenlong Chen, Ahmed Disouky, Leon Tai, Mao Mao, Brian P. Head, Marcelo G. Bonini, Jacob M. Haus, Richard D. Minshal*, Orly Lazarov

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Type 2 diabetes mellitus (T2DM) is a risk factor for the development of late-onset Alzheimer's disease (AD). However, the mechanism underlying the development of late-onset AD is largely unknown. Here we show that levels of the endothelial-enriched protein caveolin-1 (Cav-1) are reduced in the brains of T2DM patients compared with healthy aging, and inversely correlated with levels ofβ-amyloid (Aβ). Depletion of Cav-1 is recapitulated inthe brains of db/db (Leprdb) diabetic mice and corresponds with recognition memory deficits as well as the upregulation of amyloid precursor protein (APP), BACE-1, a trending increase in β-amyloid Aβ42/40 ratio and hyperphosphoryβlated tau (p-tau) species. Importantly, we show that restoration of Cav-1 levels in the brains of male db/db mice using adenovirus overexpressing Cav-1 (AAV-Cav-1) rescues learning and memory deficits and reduces pathology (i.e., APP, BACE-1 and p-tau levels). Knocking down Cav-1 using shRNA in HEK cells expressing the familial AD-linked APPswe mutant variant upregulates APP, APP carboxyl terminal fragments, and Aβ levels. In turn, rescue of Cav-1 levels restores APP metabolism. Together, these results suggest that Cav-1 regulates APP metabolism, and that depletion of Cav-1 in T2DM promotes the amyloidogenic processing of APP and hyperphosβphorylation of tau. This may suggest that depletion of Cav-1 in T2DM underlies, at least in part, the development of AD and imply that restoration of Cav-1 may be a therapeutic target for diabetic-associated sporadic AD.

Original languageEnglish (US)
Pages (from-to)8576-8583
Number of pages8
JournalJournal of Neuroscience
Volume39
Issue number43
DOIs
StatePublished - Oct 23 2019
Externally publishedYes

Keywords

  • Alzheimer's Disease
  • Amyloid
  • Caveolin-1
  • Cognition
  • Tau
  • Type 2 Diabetes

ASJC Scopus subject areas

  • Neuroscience(all)

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