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Review
. 2017 Feb 19;483(4):998-1004.
doi: 10.1016/j.bbrc.2016.09.053. Epub 2016 Sep 15.

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

Elena Popugaeva  1 , Ekaterina Pchitskaya  2 , Ilya Bezprozvanny  3
Affiliations
Review

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

Elena Popugaeva et al. Biochem Biophys Res Commun. .

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.

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.

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Figures

Figure 1
Figure 1. Ca2+ dysregulation in AD and synaptic loss
Amyloid β-peptide (Aβ) is generated by sequential cleavages of amyloid-precursor protein (APP) by β-secretase (β) and γ-secretase (γ). Aβ is able to form Ca2+-permeable pore in cell membrane. Aβ affects activity of synaptic NMDAR and mGluR5. Glutamate stimulates activation of mGluR1/5 receptors, production of IP3 and IP3R1-mediated Ca2+ release from the ER. Presenilins (PSEN) acts as Ca2+-leak pore. Many familial AD mutations disrupt this function of presenilins, which leads to ER Ca2+ overload and subsequent downregulation of neuronal store-operated calcium entry (nSOC) gated by STIM2. Increased ER Ca2+ levels result in enhanced Ca2+ release through IP3R1 and RyanR2. Dysregulated spine Ca2+ signals lead to reduction in CaMKII activity and enhanced CaN activity, subsequent facilitation of LTD and inhibition of LTP and loss of synapses. Abbreviations used in figure: AD - Alzheimer’s disease, NMDAR - N-methyl-D-aspartate receptor, mGluR1/5 - metabotropic glutamate receptor type 1 or 5, IP3 - inositol trisphosphate, IP3R1- inositol trisphosphate receptor, ER - endoplasmic reticulum, RyanR2 - ryanodine receptor type 2, CaMKII - Ca2+/calmodulin-dependent protein kinase II, CaN – calcineurin, LTD - long-term depression, LTP - long-term potentiation, Glu - glutamate.
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