Apolipoprotein E affects amyloid formation but not amyloid growth in vitro: mechanistic implications for apoE4 enhanced amyloid burden and risk for Alzheimer's disease.
The transition from the partially folded soluble Abeta monomer to insoluble Abeta amyloidfibrils is seminal to the formation and growth of amyloid plaques in Alzheimer's disease (AD). A detailed understanding of the role of AD risk factors in these processes is essential to understanding the physiochemical nature of this conformational rearrangement. The apolipoprotein E epsilon4 allele, a risk factor for AD, affects AD pathology by increasing amyloid burden relative to the much more common epsilon3 allele. In the present study, in vitro models were employed to probe the effect of these proteins on kinetically distinct steps in Abeta fibrillogenesis. Formation of Abeta amyloid was faster in the presence of apoE4 than apoE3, while growth of existing plaques was unaffected by either isoform. Further, experiments with Abeta stereoisomers establish that this effect of apoE3 is mediated through interaction with oligomeric fibrillogenic intermediates rather than through specific contacts with monomeric Abeta. Consistent with the altered pathology and enhanced risk for AD associated with inheritance of the epsilon4 allele, we conclude that APOE epsilon4 is a risk factor for AD not due to a pathological gain of function of apoE4 but to a loss of protective function of apoE3.
Esler
William P
WP
Department of Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, OH 45267-0575, USA
Marshall
Jeffrey R
JR
Stimson
Evelyn R
ER
Ghilardi
Joseph R
JR
Vinters
Harry V
HV
Mantyh
Patrick W
PW
Maggio
John E
JE
D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
D000682:Amyloid; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D020033:Protein Isoforms