Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease

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Abstract
Prostate apoptosis response-4 (Par-4) is a protein containing both a leucine zipper and a death domain that was isolated by differential screening for genes upreguiated in prostate cancer cells undergoing apoptosis1,2. Par-4 is expressed in the nervous system3, where its function is unknown. In Alzheimer disease (AD), neurons may die by apoptosis, and amyloid β-protein (Aβ) may play a role in this4–11. We 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 enhanced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherited AD.