APOE4-specific changes in Aβ accumulation in a new transgenic mouse model of Alzheimer disease.
APOE4 is the greatest risk factor for Alzheimer disease (AD) and synergistic effects with amyloid-β peptide (Aβ) suggest interactions among apoE isoforms and different forms of Aβ accumulation. However, it remains unclear how the APOE genotype affects plaque morphology, intraneuronal Aβ, soluble Aβ42, and oligomeric Aβ (oAβ), particularly in vivo. As the introduction of human APOE significantly delays amyloid deposition in transgenic mice expressing familial AD (FAD) mutations (FAD-Tg), 5xFAD-Tg mice, which exhibit amyloid deposition by age 2 months, were crossed with apoE-targeted replacement mice to produce the new EFAD-Tg mice. Compared with 5xFAD mice, Aβ deposition was delayed by ∼4 months in the EFAD mice, allowing detection of early changes in Aβ accumulation from 2-6 months. Although plaque deposition is generally greater in E4FAD mice, E2/E3FAD mice have significantly more diffuse and E4FAD more compact plaques. As a first report in FAD-Tg mice, the APOE genotypes had no effect on intraneuronal Aβ accumulation in EFAD mice. In E4FAD mice, total apoE levels were lower and total Aβ levels higher than in E2FAD and E3FAD mice. Profiles from sequential three-step extractions (TBS, detergent, and formic acid) demonstrated that the lower level of total apoE4 is reflected only in the detergent-soluble fraction, indicating that less apoE4 is lipoprotein-associated, and perhaps less lipidated, compared with apoE2 and apoE3. Soluble Aβ42 and oAβ levels were highest in E4FAD mice, although soluble apoE2, apoE3, and apoE4 levels were comparable, suggesting that the differences in soluble Aβ42 and oAβ result from functional differences among the apoE isoforms. Thus, APOE differentially regulates multiple aspects of Aβ accumulation.
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Katherine L
KL
Youmans
Leon M
LM
Tai
Evelyn
E
Nwabuisi-Heath
Lisa
L
Jungbauer
Takahisa
T
Kanekiyo
Ming
M
Gan
Jungsu
J
Kim
William A
WA
Eimer
Steve
S
Estus
G William
GW
Rebeck
Edwin J
EJ
Weeber
Guojun
G
Bu
Chunjiang
C
Yu
Mary Jo
MJ
Ladu
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D020033:Protein Isoforms