title: Calcium dysregulation, and lithium treatment to forestall Alzheimer's disease - a merging of hypotheses.
abstract: Intracellular Ca(2+) concentrations are tightly regulated, and elevated levels sustained over periods of time can cause cellular deterioration. The putative role of dysregulated intracellular Ca(2+) in Alzheimer's disease had led to the hypothesis that controlling intracellular Ca(2+) may forestall cognitive decline. Lithium has been shown to reduce intracellular Ca(2+) concentrations. Two well-characterized neuronal targets of lithium that may affect intracellular Ca(2+) levels are N-methyl-d-aspartate (NMDA) receptors and inositol monophosphatase (IMP). Results from a recent single-center placebo-controlled randomized trial suggest that long-term lithium treatment at subtherapeutic doses may have the potential to delay the progression of disease, and observational studies have shown that lithium reduces the prevalence of dementia in subjects with bipolar disorder on long-term lithium therapy. I am advancing the hypothesis that lithium may protect against cognitive decline by stabilizing intracellular Ca(2+) through a dual, synergistic mechanism of targeting both extracellular and intracellular sites, via antagonizing NMDA-receptors and inhibiting IMP. Insights derived from this hypothesis could lead to an improved understanding of the molecular pathology of Alzheimer's disease, and have implications on the evaluation and use of therapeutics that alter intracellular Ca(2+) levels.
authors.affiliation: P.O. Box 60322, Staten Island, NY 10306, USA. Electronic address: jimusa_2000@hotmail.com.
authors.forename: James
authors.initials: J
authors.lastname: Wallace
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D008962:Models, Theoretical; D009473:Neuronal Plasticity; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D008094:Lithium; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D002118:Calcium
keywords: Alzheimer's disease; Congestive heart failure Inclusion body myositis Digoxin; Inositol monophosphatase; Inositol trisphosphate; Lithium; NMDA-receptors