title: Dysregulation of neuronal calcium homeostasis in Alzheimer's disease - A therapeutic opportunity?
abstract: Alzheimer's disease (AD) is the disease of lost memories. Synaptic loss is a major reason for memory defects in AD. Signaling pathways involved in memory loss in AD are under intense investigation. The role of deranged neuronal calcium (Ca2+) signaling in synaptic loss in AD is described in this review. Familial AD (FAD) mutations in presenilins are linked directly with synaptic Ca2+signaling abnormalities, most likely by affecting endoplasmic reticulum (ER) Ca2+leak function of presenilins. Excessive ER Ca2+release via type 2 ryanodine receptors (RyanR2) is observed in AD spines due to increase in expression and function of RyanR2. Store-operated Ca2+entry (nSOC) pathway is disrupted in AD spines due to downregulation of STIM2 protein. Because of these Ca2+signaling abnormalities, a balance in activities of Ca2+-calmodulin-dependent kinase II (CaMKII) and Ca2+-dependent phosphatase calcineurin (CaN) is shifted at the synapse, tilting a balance between long-term potentiation (LTP) and long-term depression (LTD) synaptic mechanisms. As a result, synapses are weakened and eliminated in AD brains by LTD mechanism, causing memory loss. Targeting synaptic calcium signaling pathways offers opportunity for development of AD therapeutic agents.
authors.affiliation: Laboratory of Molecular Neurodegeneration, Department of Medical Physics, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russian Federation. Electronic address: lena.popugaeva@gmail.com.
authors.forename: Elena
authors.initials: E
authors.lastname: Popugaeva
authors.affiliation: Laboratory of Molecular Neurodegeneration, Department of Medical Physics, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russian Federation. Electronic address: katrincreative@yandex.ru.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Pchitskaya
authors.affiliation: Laboratory of Molecular Neurodegeneration, Department of Medical Physics, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russian Federation; Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA. Electronic address: ilya.bezprozvanny@utsouthwestern.edu.
authors.forename: Ilya
authors.initials: I
authors.lastname: Bezprozvanny
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D006706:Homeostasis; D006801:Humans; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D009474:Neurons / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin; D002118:Calcium
keywords: Alzheimer disease; Ca(2+) signaling; Ca(2+)-calmodulin-dependent kinase II (CaMKII); Calcineurin; Mushroom spines; Neuronal store-operated Ca(2+) channels; Ryanodine receptors; Synapse