The Essential Role of p53-up-regulated Modulator of Apoptosis ( Puma) and Its Regulation by FoxO3a Transcription Factor in β- Amyloid- induced Neuron Death

Background: -Amyloid-induced neuron death and degeneration is considered to be central to the pathogenesis of Alzheimer disease. Results: p53-up-regulated modulator of apoptosis (Puma), a protein of the B-cell lymphoma-2 family, is induced by transcription factor FoxO3a and participates in neuron death in response to -amyloid. Conclusion: -Amyloid-induced neuron death requires induction of Puma. Significance: Puma could be a potential target for disease therapeutics. Neurodegeneration underlies the pathology of Alzheimer disease (AD). The molecules responsible for such neurodegeneration in AD brain are mostly unknown. Recent findings indicate that the BH3-only proteins of the Bcl-2 family play an essential role in various cell death paradigms, including neurodegeneration. Here we report that Puma (p53-up-regulated modulator of apoptosis), an important member of the BH3-only protein family, is up-regulated in neurons upon toxic -amyloid 1-42 (A(1-42)) exposure both in vitro and in vivo. Down-regulation of Puma by specific siRNA provides significant protection against neuron death induced by A(1-42). We further demonstrate that the activation of p53 and inhibition of PI3K/Akt pathways induce Puma. The transcription factor FoxO3a, which is activated when PI3K/Akt signaling is inhibited, directly binds with the Puma gene and induces its expression upon exposure of neurons to oligomeric A(1-42). Moreover, Puma cooperates with another BH3-only protein, Bim, which is already implicated in AD. Our results thus suggest that Puma is activated by both p53 and PI3K/Akt/FoxO3a pathways and cooperates with Bim to induce neuron death in response to A(1-42).