Secreted β-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-κB and stabilization of calcium homeostasis

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 beta-amyloid precursor protein (APP) and/or by engaging apoptotic pathways. Alternative processing of APP in AD may increase production of neurotoxic amyloid beta-peptide (AP) and reduce production of the neuroprotective alpha-secretase-derived form of APP (sAPP alpha). In differentiated PC12 cells expressing an AD-linked PS-1 mutation (L286V), sAPP alpha activated the transcription factor NF-kappa B and prevented apoptosis induced by A beta. Treatment of cells with K beta decoy DNA blocked the antiapoptotic action of sAPP alpha, demonstrating the requirement for NF-kappa B activation in the cytoprotective action of sAPP alpha. Cells expressing mutant PS-1 exhibited an aberrant pattern of NF-kappa B activity following exposure to A beta, which was characterized by enhanced early activation of NF-kappa B followed by a prolonged depression of activity. Blockade of NF-kappa B activity in cells expressing mutant PS-1 by kappa B decoy DNA was associated with enhanced A beta-induced increases of [Ca2+](i) and mitochondrial dysfunction. Treatment of cells with sAPP alpha stabilized [Ca2+](i) and mitochondrial function and suppressed oxidative stress by a mechanism involving activation of NF-kappa B. Blockade of ER calcium release prevented (and stimulation of ER calcium release by thapsigarin 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-kappa B in preventing apoptosis induced by ER calcium release was demonstrated by data showing that sAPP alpha prevents thapsigargin-induced apoptosis, an effect blocked by kappa B decoy DNA. We conclude that sAPP alpha stabilizes cellular calcium homeostasis and protects neural cells against the proapoptotic action of mutant PS-1 by a mechanism involving activation of NF-kappa B. The data further suggest that PS-1 mutations result in aberrant NF-kappa B regulation that may render neurons vulnerable to apoptosis.