SECRETED BETA-AMYLOID PRECURSOR PROTEIN COUNTERACTS THE PROAPOPTOTIC ACTION OF MUTANT PRESENILIN-1 BY ACTIVATION OF NF-KAPPA-B 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 express ed 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 enga ging apoptotic pathways. Alternative processing of APP in AD may incre ase production of neurotoxic amyloid beta-peptide (AP) and reduce prod uction of the neuroprotective alpha-secretase-derived form of APP (sAP P alpha). In differentiated PC12 cells expressing an AD-linked PS-1 mu tation (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, demon strating the requirement for NF-kappa B activation in the cytoprotecti ve action of sAPP alpha. Cells expressing mutant PS-1 exhibited an abe rrant pattern of NF-kappa B activity following exposure to A beta, whi ch was characterized by enhanced early activation of NF-kappa B follow ed by a prolonged depression of activity. Blockade of NF-kappa B activ ity in cells expressing mutant PS-1 by kappa B decoy DNA was associate d with enhanced A beta-induced increases of [Ca2+](i) and mitochondria l dysfunction. Treatment of cells with sAPP alpha stabilized [Ca2+](i) and mitochondrial function and suppressed oxidative stress by a mecha nism involving activation of NF-kappa B. Blockade of ER calcium releas e prevented (and stimulation of ER calcium release by thapsigarin indu ced) apoptosis in cells expressing mutant PS-1, suggesting a pivotal r ole 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 c alcium release was demonstrated by data showing that sAPP alpha preven ts thapsigargin-induced apoptosis, an effect blocked by kappa B decoy DNA. We conclude that sAPP alpha stabilizes cellular calcium homeostas is and protects neural cells against the proapoptotic action of mutant PS-1 by a mechanism involving activation of NF-kappa B. The data furt her suggest that PS-1 mutations result in aberrant NF-kappa B regulati on that may render neurons vulnerable to apoptosis.