Cell and molecular neurobiology of presenilins: a role for the endoplasmic reticulum in the pathogenesis of Alzheimer's disease?
Mutations in genes encoding presenilin-1 (PS-1) and presenilin-2 (PS-2) cause many cases of autosomal dominant inherited forms of early-onset Alzheimer's disease (AD). PSs are expressed in neurons throughout the nervous system, with differences in abundance among cell populations. PS-1 and PS-2 each have six to eight transmembrane domains and are localized mainly in the endoplasmic reticulum (ER). PSs may interact with cytoskeletal proteins and beta-amyloid precursor protein (APP) in ways consistent with roles in membrane trafficking and APP processing. Expression of mutant PSs in cultured cells and transgenic mice results in increased production of an amyloidogenic-cytotoxic form of amyloid beta-peptide (Abeta). Neural cells expressing mutant PSs exhibit increased sensitivity to apoptosis induced by trophic factor withdrawal and Abeta. The proapoptotic action of mutant PSs involves perturbed calcium release from ER stores and increased levels of oxidative stress. PS mutations may also suppress neurotransmitter synthesis in cholinergic neurons, suggesting a role in regulation of neuronal phenotype. Homology of PSs with the C. elegans gene sel-12 and phenotypic similarities of PS-1 and Notch knockout mice suggest a developmental role for PSs in somitogenesis. Collectively, the emerging data suggest intriguing roles of PSs in neuronal plasticity and cell death and highlight the importance of the ER as a regulatory site involved in the pathogenesis of neuronal degeneration in AD.
Mattson
M P
MP
Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA. MMattson@aging.coa.uky.edu
Guo
Q
Q
D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D004721:Endoplasmic Reticulum / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D053764:Presenilin-1; D053766:Presenilin-2; D013347:Subcellular Fractions / Q000378:metabolism
D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2