Apolipoprotein E affects amyloid formation but not amyloid growth in vitro: Mechanistic implications for ApoE4 enhanced amyloid burden and risk for Alzheimer's disease

Abstract

The transition from the partially folded soluble Aβ monomer to insoluble Aβ amyloid fibrils 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 ϵ4 allele, a risk factor for AD, affects AD pathology by increasing amyloid burden relative to the much more common ϵ3 allele. In the present study, in vitro models were employed to probe the effect of these proteins on kinetically distinct steps in Aβ fibrillogenesis. Formation of Aβ amyloid was faster in the presence of apo E4 than apoE3, while growth of existing plaques was unaffected by either isoform. Further, experiments with Aβ stereoiso-mers establish that this effect ofapoE3 is mediated through interaction with oligomeric fibrillogenic intermediates rather than through specific contacts with monomeric Aβ. Consistent with the altered pathology and enhanced risk for AD associated with inheritance of the ϵ4 allele, we conclude that APOE ϵ4 is a risk factor for AD not due to a pathological gain of function of apo E4 but to a loss of protective function of apo E3.

Key Words:

• aggregation
• Alzheimer's disease
• amyloid
• apolipoprotein E
• deposition
• protein assembly