Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments

Abstract

The protease inhibitor alpha 1-antichymotrypsin and the lipid transport protein apolipoprotein E (apoE) are intimately associated with the 42-amino-acid beta-peptide (A beta) in the filamentous amyloid deposits of Alzheimer's disease. We report here that these two amyloid-associated proteins serve a strong stimulatory role in the polymerization of A beta into amyloid filaments. Addition of either alpha 1-anti-chymotrypsin or apoE to the A beta peptide promoted a 10- to 20-fold increase in filament formation, with apoE-4, the isoform recently linked to the development of late-onset Alzheimer's disease, showing the highest catalytic activity. These and other experiments suggest that Alzheimer amyloid deposits arise when A beta is induced to form filaments by amyloid-promoting factors (pathological chaperones) expressed in certain brain regions.

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

“…Overexpression of human ACT accelerates amyloid pathology in human APP Tg mice (Mucke et al, 2000;Nilsson et al, 2001). Although ACT functions remain unclear and some reports about biochemical interactions with Ab are controversial, most evidence argues that ACT can play a causal role in amyloid aggregation and plaque formation, which is post-Abproduction (Ma et al, 1994). mACT mRNA was reduced by ibuprofen both in vivo and in vitro.…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…E3 . E2) (Ma et al 1994;Wisniewski et al 1994;Castano et al 1995), whereas others show that apoE inhibits fibrillization (Evans et al 1994;Wood et al 1996). Conflicting results between in vitro studies may be owing to the differences in apoE and Ab preparations or other factors.…”

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

“…ApoE has been demonstrated to modulate Ah clearance and fibrillogenesis both in vitro (Beffert et al, 1999;Castano et al, 1995;Evans et al, 1994;Koistinaho et al, 2004;Ma et al, 1994;Yang et al, 1997Yang et al, , 1999 and in vivo (Bales et al, 1997;DeMattos et al, 2004;Holtzman et al, 2000;Shibata et al, 2000). In vivo, human apoE suppresses the onset of Ah deposition and subsequently results in an isoform-specific effect (E4 N E3 N E2) on the amount of Ah deposition, fibril formation, and neuritic plaque formation Holtzman et al, 2000).…”