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Volume 17, Number 11, Issue of June 1, 1997 pp. 4212-4222
Copyright ©1997 Society for Neuroscience

Alzheimer's Presenilin Mutation Sensitizes Neural Cells to Apoptosis Induced by Trophic Factor Withdrawal and Amyloid -Peptide: Involvement of Calcium and Oxyradicals

Received Feb. 12, 1997; revised March 20, 1997; accepted March 25, 1997.

Qing Guo¹, Bryce L. Sopher², Katsutoshi Furukawa¹, Dao G. Pham², Nic Robinson¹, George M. Martin², and Mark P. Mattson¹

¹ Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536, and ² Department of Pathology, University of Washington, Seattle, Washington 98195-7470

Most autosomal dominant inherited forms of early onset Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS-1) gene on chromosome 14. PS-1 is an integral membrane protein with six to nine membrane-spanning domains and is expressed in neurons throughout the brain wherein it is localized mainly in endoplasmic reticulum (ER). The mechanism or mechanisms whereby PS-1 mutations promote neuron degeneration in AD are unknown. Recent findings suggest links among deposition of amyloid -peptide (A), oxidative stress, disruption of ion homeostasis, and an apoptotic form of neuron death in AD. We now report that expression of the human PS-1 L286V mutation in PC12 cells increases their susceptibility to apoptosis induced by trophic factor withdrawal and A. Increases in oxidative stress and intracellular calcium levels induced by the apoptotic stimuli were exacerbated greatly in cells expressing the PS-1 mutation, as compared with control cell lines and lines overexpressing wild-type PS-1. The antiapoptotic gene product Bcl-2 prevented apoptosis after NGF withdrawal from differentiated PC12 cells expressing mutant PS-1. Elevations of [Ca²⁺]_i in response to thapsigargin, an inhibitor of the ER Ca²⁺-ATPase, were increased in cells expressing mutant PS-1, and this adverse effect was abolished in cells expressing Bcl-2. Antioxidants and blockers of calcium influx and release from ER protected cells against the adverse consequences of the PS-1 mutation. By perturbing cellular calcium regulation and promoting oxidative stress, PS-1 mutations may sensitize neurons to apoptotic death in AD.

Key words: Alzheimer's disease; antioxidant; bcl-2; dantrolene; endoplasmic reticulum; fura-2; nerve growth factor

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