AGGREGATED AMYLOID-BETA PROTEIN INDUCES CORTICAL NEURONAL APOPTOSIS AND CONCOMITANT APOPTOTIC PATTERN OF GENE INDUCTION

To gain a molecular understanding of neuronal responses to amyloid-bet a peptide (A beta), we have analyzed the effects of A beta treatment o n neuronal gene expression in vitro by quantitative reverse transcript ion-PCR and in situ hybridization. Treatment of cultured rat cortical neurons with A beta(1-40) results in a wide-spread apoptotic neuronal death. Associated with death is an induction of several members of the immediate early gene family. Specifically, we (1) report the time-dep endent and robust induction of c-jun, junB, c-fos, and fosB, as well a s transin, which is induced by c-Jun/c-Fos heterodimers and encodes an extracellular matrix protease; these gene inductions appear to be sel ective because other Jun and Fos family members, i.e., junD and fra-1, are induced only marginally; (2) show that the c-jun induction is wid espread, whereas c-fos expression is restricted to a subset of neurons , typically those with condensed chromatin, which is a hallmark of apo ptosis; (3) correlate gene induction and neuronal death by showing tha t each has a similar dose-response to A beta; and (4) demonstrate that both cell death and immediate early gene induction are dependent on A beta aggregation state. This overall gene expression pattern during t his ''physiologically inappropriate'' apoptotic stimulus is markedly s imilar to the pattern we previously identified after a ''physiological ly appropriate'' stimulus, i.e., the NGF deprivation-induced death of sympathetic neurons. Hence, the parallels identified here further our understanding of the genetic alterations that may lead neurons to apop tosis in response to markedly different insults.