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Network-wide dysregulation of calcium homeostasis in Alzheimer’s disease

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Abstract

Dysregulation of intracellular Ca2+ homeostasis has been proposed as a common proximal cause of neural dysfunction during aging and Alzheimer’s disease (AD). In this context, aberrant Ca2+ signaling has been viewed as a neuronal phenomenon mostly related to the dysfunction of intracellular Ca2+ stores. However, recent data suggest that, in AD, Ca2+ dyshomeostasis is not restricted to neurons but represents a global phenomenon affecting virtually all cells in the brain. AD-related aberrant Ca2+ signaling in astrocytes and microglia, which is activated during the disease, probably contributes profoundly to an inflammatory response that, in turn, impacts neuronal Ca2+ homeostasis and brain function. Based on recent data obtained in vivo and in vitro, we propose that bidirectional interactions between the inflammatory responses of glial cells and aberrant Ca2+ signaling represent a vicious cycle accelerating disease progression.

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Abbreviations

AD:

Alzheimer’s disease

AMPA:

α-Amino-3-hydroxy-5-methylisoxazole-4-proprionic acid

APP:

Amyloid precursor protein

Aβ:

Amyloid β

[Ca2+]e :

Extracellular free Ca2+ concentration

[Ca2+]i :

Intracellular free Ca2+ concentration

CaN:

Calcineurin

DICT:

Damage-induced Ca2+ transient

GABA:

Gamma-aminobutyric acid

IFN-γ:

Interferon-γ

IL:

Interleukin

IP3 :

Inositol trisphosphate

IP3R:

Inositol trisphosphate receptor

LPS:

Lipopolysaccharide

NFAT:

Nuclear factor of activated T-cells

NLRP3:

Nucleotide binding and oligomerization domain-like receptor family pyrin domain containing 3

NMDA:

N-methyl-D-aspartate

NO:

Nitric oxide

PS:

Presenilin

RANTES:

Regulated on activation, normal T cell expressed and secreted

RyR:

Ryanodine receptor

TNF-α:

Tumor necrosis factor-α

WT:

Wild-type

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Acknowledgement

We thank A. Kaupp for technical assistance. A recent in vivo study reports a profound dysregulation of intracellular Ca2+ homeostasis in plaque-associated microglia (Brawek et al. (2014) Impairment of in vivo calcium signaling in amyloid plaque-associated microglia. Acta Neuropathol in press).

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  1. Institute of Physiology II, Eberhard Karls University of Tübingen, Keplerstrasse 15, 72074, Tübingen, Germany

    Bianca Brawek & Olga Garaschuk

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  1. Bianca Brawek
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  2. Olga Garaschuk
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Correspondence to Olga Garaschuk.

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This work was supported by CIN (Werner Reichardt Center for Integrative Neuroscience).

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Brawek, B., Garaschuk, O. Network-wide dysregulation of calcium homeostasis in Alzheimer’s disease. Cell Tissue Res 357, 427–438 (2014). https://doi.org/10.1007/s00441-014-1798-8

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  • DOI: https://doi.org/10.1007/s00441-014-1798-8

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