Mutations in the presenilin-1 (PS-1) gene account for approximately 50% of the cases of autosomal dominant, early onset, inherited forms of Alzheimer's disease (AD). PS-1 is an integral membrane protein expressed in neurons and is localized primarily in the endoplasmic reticulum (ER). PS-1 mutations may promote neuronal degeneration by altering the processing of the β-amyloid precursor protein (APP) and/or by engaging apoptotic pathways. Alternative processing of APP in AD may increase production of neurotoxic amyloid β-peptide (Aβ) and reduce production of the neuroprotective α- secretase-derived form of APP (sAPPα). In differentiated PC12 cells expressing an AD-linked PS-1 mutation (L286V), sAPPα activated the transcription factor NF-κB and prevented apoptosis induced by Aβ. Treatment of cells with κB decoy DNA blocked the antiapoptotic action of sAPPα, demonstrating the requirement for NF-κB activation in the cytoprotective action of sAPPα. Cells expressing mutant PS-1 exhibited an aberrant pattern of NF-κB activity following exposure to Aβ, which was characterized by enhanced early activation of NF-κB followed by a prolonged depression of activity. Blockade of NF-κB activity in cells expressing mutant PS-1 by κB decoy DNA was associated with enhanced Aβ-induced increases of [Ca2+](i) and mitochondrial dysfunction. Treatment of cells with sAPPα stabilized [Ca2+](i) and mitochondrial function and suppressed oxidative stress by a mechanism involving activation of NF-κB. Blockade of ER calcium release prevented (and stimulation of ER calcium release by thapsigargin induced) apoptosis in cells expressing mutant PS-1, suggesting a pivotal role for ER calcium release in the proapoptotic action of mutant PS-1. Finally, a role for NF-κB in preventing apoptosis induced by ER calcium release was demonstrated by data showing that sAPPα prevents thapsigargin-induced apoptosis, an effect blocked by κB decoy DNA. We conclude that sAPPα stabilizes cellular calcium homeostasis and protects neural cells against the proapoptotic action of mutant PS-1 by a mechanism involving activation of NF- κB. The data further suggest that PS-1 mutations result in aberrant NF-κB regulation that may render neurons vulnerable to apoptosis.
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