Dysregulation of neuronal calcium homeostasis in Alzheimer's disease - A therapeutic opportunity?

Elena Popugaeva, Ekaterina Pchitskaya, Ilya Bezprozvanny

Research output: Contribution to journalArticle

48 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBiochemical and Biophysical Research Communications
DOIs
StateAccepted/In press - Sep 6 2016

Fingerprint

Alzheimer Disease
Homeostasis
Calcium
Presenilins
Calcium Signaling
Therapeutics
Data storage equipment
Memory Disorders
Endoplasmic Reticulum
Synapses
Spine
Long-Term Synaptic Depression
Calcium-Calmodulin-Dependent Protein Kinases
Ryanodine Receptor Calcium Release Channel
Long-Term Potentiation
Calmodulin
Down-Regulation
Brain
Phosphotransferases
Depression

Keywords

  • Alzheimer disease
  • Ca signaling
  • Ca-calmodulin-dependent kinase II (CaMKII)
  • Calcineurin
  • Mushroom spines
  • Neuronal store-operated Ca channels
  • Ryanodine receptors
  • Synapse

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Dysregulation of neuronal calcium homeostasis in Alzheimer's disease - A therapeutic opportunity? / Popugaeva, Elena; Pchitskaya, Ekaterina; Bezprozvanny, Ilya.

In: Biochemical and Biophysical Research Communications, 06.09.2016.

Research output: Contribution to journalArticle

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