PAR-4 IS A MEDIATOR OF NEURONAL DEGENERATION ASSOCIATED WITH THE PATHOGENESIS OF ALZHEIMER-DISEASE

Prostate apoptosis response-4 (Par-4) is a protein containing both a l eucine zipper and a death domain that was isolated by differential scr eening for genes upregulated in prostate cancer cells undergoing apopt osis(1,2). Par-4 is expressed in the nervous system(3), where its func tion is unknown. In Alzheimer disease (AD), neurons may die by apoptos is, and amyloid beta-protein (A beta) may play a role in this(4-11). W e report here that Par-4 expression is increased in vulnerable neurons in AD brain and is induced in cultured neurons undergoing apoptosis. Blockade of Par-4 expression or function prevented neuronal apoptosis induced by Ab and trophic factor withdrawl. Par-4 expression was enhan ced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherit ed AD.