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Astrocyte activation and neurovascular function in a diet‐based model of vascular contributions to cognitive impairment and dementia (VCID)
Author(s) -
Sompol Pradoldej,
Edelmann Stephanie E.,
Lin RueiLung,
Gant Christopher C.,
Kraner Susan D.,
Weiss Blaine E.,
Farr N. Drew,
Gollihue Jenna L.,
Thibault Olivier,
Wilcock Donna M.,
Norris Christopher M.
Publication year - 2020
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 - 10.1002/alz.043618
Subject(s) - astrocyte , calcineurin , hyperhomocysteinemia , nfat , medicine , endocrinology , neuroscience , homocysteine , biology , transplantation , central nervous system
Background Vascular contributions to cognitive impairment and dementia (VCID) are highly comorbid with Alzheimer’s disease (AD) pathology and may accelerate the progression of dementia and/or reduce the clinical efficacy of anti‐AD treatments. Neurotoxic astrocyte activation linked to aberrant calcineurin/NFAT signaling is a shared mechanism between VCID and AD. Recently, hyperhomocysteinemia, a major risk factor for VCID and a variety of other vascular‐related diseases, was linked to astrocyte dysfunction and calcineurin/NFAT hyperactivation. However, causal relationships between astrocytes and neurovascular dysfunction under hyperhomocysteine conditions has yet to be determined. Here, we investigate the hypothesis that diet‐induced hyperhomocysteinemia disrupts cerebrovascular function, in part, through an astrocyte‐based calcineurin/NFAT mechanism. Method Wild type mice (2‐3 months‐of‐age) received intracortical injections of adeno associated virus (AAV) equipped with an astrocyte‐specific promoter to target astrocytes with EGFP (control) or VIVIT‐EGFP, to inhibit the calcineruin/NFAT pathway. A chronic, glass cranial window was then installed for longitudinal multiphoton imaging of astrocytes and cerebrovascular parameters in barrel cortex. Three weeks post‐surgery, mice were fed with control or hyperhomocysteinemia‐inducing diet (low levels of folate, vitamins B6 and B12 and enriched with methionine) for 12 weeks. Astrocytic EGFP volume, microvessel leakage, and functional hyperemia (during whisker stimulation) were measured in the same brain region before and after 12 weeks of diet treatment. Result Upregulation of astrocytic EGFP volume developed during hyperhomocysteinemia consistent with astrocyte activation. This change was attenuated by CN/NFAT inhibition with VIVIT, similar to previous observations in amyloidogenic mice. Hyperemic capillary responses to whisker stimulation in barrel cortex were also reduced with the development of hyperhomocysteinemia, suggesting an impairment of cerebrovascular function. Microvessel integrity (leakage) and the role of astrocytic NFATs are currently under investigation. Conclusion The results indicate that hyperhomocysteinemia, a major risk factor for VCID, may trigger a neurotoxic activated astrocyte phenotype leading to neurovascular injury, and ultimately cognitive decline.