Apolipoprotein is required for the formation of filamentous amyloid, but not for amorphous Abeta deposition, in an AbetaPP/PS double transgenic mouse model of Alzheimer's disease.
To determine the role of apolipoprotein E (apoE) in the deposition of different forms of Alzheimer amyloid deposit, we studied mice expressing both mutant human amyloid beta-protein precursor (AbetaPP) and presenilin 1 (PS1) that, in addition, were either normal or knocked-out for apoE. By 7 months of age, extensive deposits of amorphous amyloid beta (Abeta) had developed equally in both lines, indicating that, when present in high amounts, Abeta alone is sufficient for such deposition to occur. In contrast, filamentous, thioflavine S-positive amyloid deposition in AbetaPP/PS mice was catalyzed at least 3000 fold by apoE. Electron micrographs further illustrated the filamentous nature of Abeta deposits in mice expressing apoE. These and other behavior data indicate that the primary function of apoE in Alzheimer's disease is to promote the polymerization of Abeta into mature, beta pleated sheet filaments, a process that is necessary for inducing cognitive decline. Thus, preventing apoE from binding to Abeta may prove to be an effective means of therapeutic intervention.
Costa
David A
DA
Department of Biochemistry and Molecular Biology and Suncoast Gerontology Center, University of South Florida, Tampa, FL 33620, USA.
Nilsson
Lars N G
LN
Bales
Kelly R
KR
Paul
Steven M
SM
Potter
Huntington
H
D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism / Q000502:physiology*; D052160:Benzothiazoles; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D013844:Thiazoles / Q000378:metabolism
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D052160:Benzothiazoles; D007381:Intermediate Filament Proteins; D013844:Thiazoles; C009462:thioflavin T