Aberrant presenilin-1 expression downregulates LDL receptor-related protein (LRP): Is LRP central to Alzheimer's disease pathogenesis?

Low density lipoprotein receptor-related protein (LRP) polymorphisms have r ecently been associated with an increased susceptibility of Alzheimer's dis ease (AD). Furthermore, LRP has been linked to molecules that confer suscep tibility to AD (apolipoprotein E, alpha-2-macroglobulin, amyloid precursor protein), previously with the exception of the presenilins. Here we report that aberrant presenilin-1 expression in vivo and in vitro downregulates LR P. Specifically, transgenic mice overexpressing the M146L or L286V presenil in-1 mutation show decreased levels of LRP expression in neuronal populatio ns where presenilin-1 and LRP are closely colocalized or coexpressed. Moreo ver, cell lines transfected with presenilin-1 also expressed decreased leve ls of LRP. These findings suggest that LRP may be central to AD pathogenesi s since all proteins genetically associated with AD can now be linked via a single pathway to LRP.