Aggregated amyloid-β protein induces cortical neuronal apoptosis and concomitant 'apoptotic' pattern of gene induction

To gain a molecular understanding of neuronal responses to amyloid-β peptide (Aβ), we have analyzed the effects of Aβ treatment on neuronal gene expression in vitro by quantitative reverse transcription-PCR and in situ hybridization. Treatment of cultured rat cortical neurons with Aβ_1-40 results in a widespread apoptotic neuronal death. Associated with death is an induction of several members of the immediate early gene family. Specifically, we (1) report the time-dependent and robust induction of c- jun, junB, c-fos, and foaB, as well as transin, which is induced by c-Jun/c- Fos heterodimers and encodes an extracellular matrix protease; these gene inductions appear to be selective 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 widespread, whereas c-fos expression is restricted to a subset of neurons, typically those with condensed chromatin, which is a hallmark of apoptosis; (3) correlate gene induction and neuronal death by showing that each has a similar dose-response to Aβ; and (4) demonstrate that both cell death and immediate early gene induction are dependent on Aβ aggregation state. This overall gene expression pattern during this 'physiologically inappropriate' apoptotic stimulus is markedly similar to the pattern we previously identified after a 'physiologically 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 apoptosis in response to markedly different insults.