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

To date, mutations in three genes, β‐amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2), have been found to be causally related to familial Alzheimer's disease (AD). In addition, polymorphisms in three other genes (among others), apolipoprotein E (apoE), alpha2‐macroglobulin (αm), and the low density lipoprotein receptor‐related protein (LRP), are implicated to contribute to AD pathogenesis. Interestingly, the encoded gene products are all functionally related in various ways to LRP. Specifically apoE, α2m, secreted APP, and amyloid β‐protein (Aβ) complexed to either apoE or α2m are ligands of LRP. Furthermore, over‐expression 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 ligands are present in senile plaques, decreased LRP function may be a central component in AD pathogenesis. This review explores the current knowledge of LRP in AD and its relationship to the other known AD susceptibility markers. Microsc. Res. Tech. 50:268–272, 2000. © 2000 Wiley‐Liss, Inc.