title: Presenilin mutations and calcium signaling defects in the nervous and immune systems.
abstract: Presenilin-1 (PS1) is thought to regulate cell differentiation and survival by modulating the Notch signaling pathway. Mutations in PS1 have been shown to cause early-onset inherited forms of Alzheimer's disease (AD) by a gain-of-function mechanism that alters proteolytic processing of the amyloid precursor protein (APP) resulting in increased production of neurotoxic forms of amyloid beta-peptide. The present article considers a second pathogenic mode of action of PS1 mutations, a defect in cellular calcium signaling characterized by overfilling of endoplasmic reticulum (ER) calcium stores and altered capacitive calcium entry; this abnormality may impair synaptic plasticity and sensitize neurons to apoptosis and excitotoxicity. The calcium signaling defect has also been documented in lymphocytes, suggesting a contribution of immune dysfunction to the pathogenesis of AD. A better understanding of the calcium signaling defect resulting from PS1 mutations may lead to the development of novel preventative and therapeutic strategies for disorders of the nervous and immune systems.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, MD 21224, USA. mattsonm@grc.nia.nih.gov
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
authors.forename: S L
authors.initials: SL
authors.lastname: Chan
authors.forename: S
authors.initials: S
authors.lastname: Camandola
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics*; D006801:Humans; D007107:Immune System / Q000503:physiopathology; D008214:Lymphocytes / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008954:Models, Biological; D009154:Mutation; D009420:Nervous System / Q000503:physiopathology; D053764:Presenilin-1; D051880:Receptors, Notch
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051880:Receptors, Notch