PRESENILINS, THE ENDOPLASMIC-RETICULUM, AND NEURONAL APOPTOSIS IN ALZHEIMERS-DISEASE

Many cases of autosomal dominant inherited forms of early-onset Alzhei mer's disease are caused by mutations in the genes encoding presenilin -1 (PS-1; chromosome 14) and presenilin-2 (PS-2; chromosome 1). PSs ar e expressed in neurons throughout the brain wherein they appear to be localized primarily to the endoplasmic reticulum (ER) of cell bodies a nd dendrites. PS-1 and PS-2 show high homology and are predicted to ha ve eight transmembrane domains with the C terminus, N terminus, and a loop domain all on the cytosolic side of the membrane; an enzymatic cl eavage of PSs occurs at a site near the loop domain. The normal functi on of PSs is unknown, but data suggest roles in membrane trafficking, amyloid precursor protein processing, and regulation of ER calcium hom eostasis. Homology of PSs to the C. elegans gene sel-12, which is invo lved in Notch signaling, and phenotypic similarities of PS-1 and Notch knockout mice suggest a developmental role for PSs in the nervous sys tem. When expressed in cultured cells and transgenic mice, mutant PSs promote increased production of a long form of amyloid beta-peptide (A beta 1-42) that may possess enhanced amyloidogenic and neurotoxic pro perties, PS mutations sensitize cultured neural cells to apoptosis ind uced by trophic factor withdrawal, metabolic insults, and amyloid beta -peptide. The mechanism responsible for the proapoptotic action of mut ant PSs may involve perturbed calcium release from ER stores and incre ased levels of oxidative stress. Recent studies of apoptosis in many d ifferent cell types suggest that ER calcium signaling can modulate apo ptosis. The evolving picture of PS roles in neuronal plasticity and Al zheimer's disease is bringing to the forefront the ER, an organelle in creasingly recognized as a key regulator of neuronal plasticity and su rvival.