RRC ID 73729
Author Honda K, Saito Y, Saito H, Toyoda M, Abe R, Saito T, Saido TC, Michikawa M, Taru H, Sobu Y, Hata S, Nakaya T, Suzuki T.
Title 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.
Journal Neurobiol Aging
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.
Volume 123
Pages 63-74
Published 2023-3-1
DOI 10.1016/j.neurobiolaging.2022.12.003
PII S0197-4580(22)00257-3
PMID 36638682
MeSH 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
IF 4.347
Mice RBRC06344 RBRC03390 RBRC03418