Consequences of the molecular mechanism of amyloid formation for the understanding of the pathogenesis of Alzheimer's disease and the development of therapeutic strategies
Lansbury, P.T.
Arzneimittel-Forschung 45(3a): 432-434
1995
ISSN/ISBN: 0004-4172 PMID: 7763339 Document Number: 441674
Amyloid formation in the brain is diagnostic of Alzheimer's disease (AD). However, it is not known whether amyloidogenesis precedes and possibly causes cell death or is a byproduct of cell lysis. In any event, it is critical to understand the time course of amyloid formation. The mechanism of amyloidogenesis has been studied in a simple in vitro model system which can be modified to dissect the factors which may be important in vivo. The studies described herein deal with two factors which are known to be important in vivo; the length of the beta protein C-terminus and the endogenous molecule apolipoprotein E (apoE). It could be shown that the C-terminal sequence of the beta-amyloid protein is a critical determinant of the rate of amyloid formation. This discovery led us to propose that the production of the C-terminally extended variants may be a pathogenic event in familial AD. The APOE allele has been shown to be a susceptibility factor for non-familial AD. The apoE variants have been shown to be amyloid nucleation inhibitors. These proteins probably serve as endogenous amyloid suppressors.