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PL‐04‐01: Calcium dysregulation in Alzheimer's disease
Author(s) -
Bacskai Brian J.
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.05.481
Subject(s) - calcium , calcium in biology , calcium imaging , neuroscience , calcium signaling , astrocyte , biology , microbiology and biotechnology , calcium metabolism , intracellular , medicine , central nervous system
Background: Alzheimer’s disease is characterized by the deposition of senile plaques in the brain resulting in focal neurotoxicity that ultimately leads to neural network disruption. Intracellular calcium is a tightly regulated second messenger whose activation leads to numerous downstream events, including cell death. It has been suggested that dysregulation of calcium homeostasis plays a role in Alzheimer’s disease, however this has not been demonstrated directly. Methods: We combined in vivo multiphoton cell-resolved calcium imaging to quantitatively image resting and dynamic calcium signaling in both neurons and astrocytes in the brains of mouse models of AD. Results: We found that resting calcium was upregulated in neurons and throughout the astrocytic network in mice with cortical plaques. This increase in calcium levels in neurons, but not astrocytes, depended on the proximity to individual senile plaques. The neuronal calcium overload was not the result of presenilin mutations, and led to the loss of spino-dendritic compartmentalization, important for synaptic coordination. We also observed increased spontaneous calcium transients in astrocytes that were not dependent on neuronal activity. Astrocytes were functionally coupled across long distances in APP mice but not wildtype mice with evidence of in vivo intercellular calcium waves originating near plaques and spreading to astrocytes nearly 200 microns away. Conclusions: These data reveal disruptions in calcium homeostasis in both neurons and astrocytes in mouse models of AD with differing spatial associations. Together, the results demonstrate that the aberrant intracellular calcium levels in the brain provide insight into the pathophysiology of AD and that specific manipulation of calcium levels may lead to new drug targets.