Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer's disease

Mark P. Mattson, Qing Guo, Katsutoshi Furukawa, Ward A. Pedersen

Research output: Contribution to journalReview articlepeer-review

226 Citations (Scopus)

Abstract

Many cases of autosomal dominant inherited forms of early-onset Alzheimer's disease are caused by mutations in the genes encoding presenilin- 1 (PS-1; chromosome 14) and presenilin-2 (PS-2; chromosome 1). PSs are expressed in neurons throughout the brain wherein they appear to be localized primarily to the endoplasmic reticulum (ER) of cell bodies and dendrites. PS- 1 and PS-2 show high homology and are predicted to have eight transmembrane domains with the C terminus, N terminus and a loop domain all on the cytosolic side of the membrane; an enzymatic cleavage of PSs occurs at a site near the loop domain. The normal function of PSs is unknown, but data suggest roles in membrane trafficking, amyloid precursor protein processing, and regulation of ER calcium homeostasis. Homology of PSs to the C. elegans gene sel-12, which is involved in Notch signaling, and phenotypic similarities of PS-1 and Notch knockout mice suggest a developmental role for PSs in the nervous system. When expressed in cultured cells and transgenic mice, mutant PSs promote increased production of a long form of amyloid β-peptide (Aβ1- 42) that may possess enhanced amyloidogenic and neurotoxic properties. PS mutations sensitize cultured neural cells to apoptosis induced by trophic factor withdrawal, metabolic insults, and amyloid β-peptide. The mechanism responsible for the proapoptotic action of mutant PSs may involve perturbed calcium release from ER stores and increased levels of oxidative stress. Recent studies of apoptosis in many different cell types suggest that ER calcium signaling can modulate apoptosis. The evolving picture of PS roles in neuronal plasticity and Alzheimer's disease is bringing to the forefront the ER, an organelle increasingly recognized as a key regulator of neuronal plasticity and survival.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalJournal of Neurochemistry
Volume70
Issue number1
DOIs
Publication statusPublished - 1998 Jan

Keywords

  • Amyloid precursor protein
  • Amyloid β-peptide
  • Apoptosis
  • Calcium homeostasis
  • Inositol trisphosphate
  • Muscarinic cholinergic
  • Nerve growth factor
  • Reactive oxygen species
  • Vitamin E

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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