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O4‐04‐05: Calcineurin: A dual threat in aging and Alzheimer's disease
Author(s) -
Norris Christopher M.,
Abdul Hafiz Mohmmad,
Furman Jennifer L.,
Sama Michelle A.,
Mathis Diana M.
Publication year - 2010
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.2010.05.485
Subject(s) - nfat , calcineurin , neuroscience , hippocampal formation , long term potentiation , cognitive decline , microbiology and biotechnology , synaptic plasticity , hippocampus , biology , inflammation , dementia , immunology , disease , medicine , biochemistry , transplantation , receptor
Background: The protein phosphatase, calcineurin (CN) regulates numerous and diverse cellular processes via activation of NFAT transcription factors (Nuclear Factor of Activated T cells). We recently discovered that different CN-dependent NFAT isoforms selectively accumulate in hippocampal nuclear fractions during different stages of dementia and Alzheimer’s disease (AD). Some changes occurred at very mild stages of cognitive decline and/ or progressed as dementia worsened, suggesting that augmented CN signaling is part of the pathophysiology of AD. CN is abundant in neurons and responds rapidly to elevated amyloid levels, leading to alterations in structural and functional synaptic plasticity. Neuronal CN signaling may therefore be a useful molecular target for treating AD-related cognitive decline. In addition, CN can appear at high levels in astrocytes (especially those that are activated during injury, aging, and/or amyloid pathology), where it uses NFATs to coordinate several immune/inflammatory cascades relevant to neurodegenerative disease. The goal of the present study is to tease apart the cell-type specific involvement of the CN/NFAT pathway in altered neurologic function using an animal model of AD. Methods: The NFAT inhibitor VIVIT, or an EGFP control construct, is selectively expressed in hippocampal astrocytes of double knock-in APP/PS1 mice using adeno-associated virus 2/5 (AAV2/5) that encodes the human GFAP promoter, Gfa2. Biomarkers of synaptic function in acute hippocampal slices (e.g. basal synaptic strength, longterm potentiation and depression), inflammation (cytokine expression, GFAP expression), and amyloid pathology are measured at various time points after infection by lab members who are blind to experimental treatments. Results: Preliminary studies on 18 mos APP/PS1 mice, infected for two months with AAV2/5, reveal rapidly decaying LTP (i.e. across 1 h) in hippocampi treated with Gfa2-EGFP (115 6 9% of baseline at 1 h post-induction), but not in hippocampi treated with AAV2/5-Gfa2-VIVIT (138 6 8%, p < 0.01). Gfa2VIVIT-treated hippocampi also show greater basal CA1 synaptic strength. Analysis of other biomarkers is underway. Conclusions: Blockade of CN/ NFAT signaling, selectively in astrocytes, may prevent or reverse synaptic deficits associated with amyloid pathology. The results suggest that astrocyte activation, due in part to elevated astrocytic CN signaling, plays an important role in driving or maintaining neuronal dysfunction during AD.