LDL receptor-related protein (LRP) in Alzheimer's disease: Towards a unified theory of pathogenesis

To date, mutations in three genes, beta-amyloid precursor protein (APP), pr esenilin 1 (PS1), and presenilin 2 (PS2), have been found to be causally re lated to familial Alzheimer's disease (AD). In addition, polymorphisms in t hree other genes (among others), apolipoprotein E (apoE), alpha2-macroglobu lin (alpha m), and the low density lipoprotein receptor-related protein (LR P), are implicated to contribute to AD pathogenesis. Interestingly, the enc oded gene products are all functionally related in various ways to LRP. Spe cifically apoE, alpha 2m, secreted APP, and amyloid beta-protein (Ap) compl exed to either apoE or alpha 2m are ligands of LRP. Furthermore, over-expre ssion of presenilin 1 results in decreased expression of LRP. Since levels of many LRP ligands are increased in Alzheimer's disease and LRP and its li gands are present in senile plaques, decreased LRP function may be a centra l, component in AD pathogenesis. This review explores the current knowledge of LRP in AD and its relationship to the other known AD susceptibility mar kers. (C) 2000 Wiley-Liss, Inc.