The role of ATF4 in amyloid-beta-induced neuronal death.
Abstract
Alzheimer’s disease (AD) is partially characterized by excessive accumulation of amyloid-b (Ab) in the brain. Ab oligomers have greater toxicity than Ab fibrils and induce neuronal stress. The Integrated Stress Response (ISR) is activated in response to cellular stress and increases expression of activating transcription factor 4 (ATF4) and its target genes. Prolonged activation has been shown to induce aberrant cell death, and increased markers of the ISR have been found in the brains of AD patients. However, the exact mechanism of amyloid-b-induced death is largely unknown. We aimed to determine if Ab-induced neuronal death occurs through ATF4-mediated upregulation of its downstream pro-apoptotic gene PUMA. Primary cortical neurons were treated with Ab oligomers. Ab induced apoptosis in a PUMA-dependent manner in the presence of ATF4. These results suggest that therapeutics targeting ATF4 and PUMA may be successful in alleviating excessive neuronal death induced by amyloid-b in Alzheimer’s disease.