TY - JOUR
T1 - Human and murine apoE markedly alters Aβ metabolism before and after plaque formation in a mouse model of Alzheimer's Disease
AU - Fagan, Anne M.
AU - Watson, Melanie
AU - Parsadanian, Maia
AU - Bales, Kelly R.
AU - Paul, Steven M.
AU - Holtzman, David M.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) Grants AG00861-01 and AG05681-16 (A.M.F.) and AG13956 and AG11355 (D.M.H.). We thank Robert Brendza, Guojun Bu, Ron Demattos, Todd Golde, and Suzanne Wharle for helpful comments.
PY - 2002
Y1 - 2002
N2 - The ε4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD), perhaps through effects on amyloid-β (Aβ) metabolism. Detailed analyses of various Aβ parameters in aging APPV717F+/-transgenic mice expressing mouse apoE, no apoE, or human apoE2, apoE3, or apoE4 demonstrate that apoE facilitates, but is not required for, Aβ fibril formation in vivo. Human apoE isoforms markedly delayed Aβ deposition relative to mouse apoE, with apoE2 (and apoE3 to a lesser extent) having a prolonged ability to prevent Aβ from converting into fibrillar forms. Isoform-specific effects of human apoE on Aβ levels and neuritic plaque formation mimicked that observed in AD (E4 > E3 > E2). Importantly, observation of an apoE-dependent decrease in percent soluble Aβ and enrichment of Aβ in membrane microdomains prior to Aβ deposition indicates that apoE influences Aβ metabolism early in the amyloidogenic process and provides a possible novel mechanism by which apoE affects AD pathogenesis.
AB - The ε4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD), perhaps through effects on amyloid-β (Aβ) metabolism. Detailed analyses of various Aβ parameters in aging APPV717F+/-transgenic mice expressing mouse apoE, no apoE, or human apoE2, apoE3, or apoE4 demonstrate that apoE facilitates, but is not required for, Aβ fibril formation in vivo. Human apoE isoforms markedly delayed Aβ deposition relative to mouse apoE, with apoE2 (and apoE3 to a lesser extent) having a prolonged ability to prevent Aβ from converting into fibrillar forms. Isoform-specific effects of human apoE on Aβ levels and neuritic plaque formation mimicked that observed in AD (E4 > E3 > E2). Importantly, observation of an apoE-dependent decrease in percent soluble Aβ and enrichment of Aβ in membrane microdomains prior to Aβ deposition indicates that apoE influences Aβ metabolism early in the amyloidogenic process and provides a possible novel mechanism by which apoE affects AD pathogenesis.
UR - http://www.scopus.com/inward/record.url?scp=0036233168&partnerID=8YFLogxK
U2 - 10.1006/nbdi.2002.0483
DO - 10.1006/nbdi.2002.0483
M3 - Article
C2 - 11950276
AN - SCOPUS:0036233168
SN - 0969-9961
VL - 9
SP - 305
EP - 318
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -