Accumulation of amyloid-β in the brain of mouse models of Alzheimer's disease is modified by altered gene expression in the presence of human apoE isoforms during aging

Neurobiol Aging. 2023 Mar:123:63-74. doi: 10.1016/j.neurobiolaging.2022.12.003. Epub 2022 Dec 17.

Abstract

Apolipoprotein E4 (apoE4) is a risk factor for Alzheimer's disease (AD). Here, we investigated brain amyloid-β (Aβ) accumulation throughout the aging process in an amyloid precursor protein (APP) knock-in (KI) mouse model of AD that expresses human APPNL-G-F with or without human apoE4 or apoE3. Brain Aβ42 levels were significantly lower in 9-month-old mice that express human isoforms of apoE than in age-matched APP-KI control mice. Linear accumulation of Aβ42 began in 5-month-old apoE4 mice, and a strong increase in Aβ42 levels was observed in 21-month-old apoE3 mice. Aβ42 levels in cerebroventricular fluid were higher in apoE3 than in apoE4 mice at 6-7 months of age, suggesting that apoE3 is more efficient at clearing Aβ42 than apoE4 at these ages. However, apoE3 protein levels were lower than apoE4 protein levels in the brains of 21-month-old apoE3 and apoE4 mice, respectively, which may explain the rapid increase in brain Aβ42 burden in apoE3 mice. We identified genes that were downregulated in a human apoE-dependent (apoE4 > apoE3) and age-dependent (apoE3 = apoE4) manner, which may regulate brain Aβ burden and/or AD progression. Analysis of gene expression in AD mouse models helps identify molecular mechanisms of pleiotropy by the human APOE gene during aging.

Keywords: Alzheimer's disease; Amyloid-β; Apolipoprotein E; Brain aging; Gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Apolipoprotein E3 / genetics
  • Apolipoprotein E3 / metabolism
  • Apolipoprotein E4 / genetics
  • Apolipoprotein E4 / metabolism
  • Apolipoproteins E / metabolism
  • Brain / metabolism
  • Gene Expression
  • Humans
  • Mice
  • Mice, Transgenic
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism

Substances

  • Apolipoprotein E4
  • Apolipoprotein E3
  • Apolipoproteins E
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Protein Isoforms