Targeting Astrocyte Signaling Alleviates Cerebrovascular and Synaptic Function Deficits in a Diet-Based Mouse Model of Small Cerebral Vessel Disease

Abstract

Despite the indispensable role that astrocytes play in the neurovascular unit, few studies have investigated the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology. Diet-mediated induction of hyperhomocysteinemia (HHcy) recapitulates numerous features of vascular contributions to cognitive impairment and dementia (VCID). Here, we used astrocyte targeting approaches to evaluate astrocyte Ca2+dysregulation and the impact of aberrant astrocyte signaling on cerebrovascular dysfunction and synapse impairment in male and female HHcy diet mice. Two-photon imaging carried out in fully awake mice revealed activity-dependent Ca2+dysregulation in barrel cortex astrocytes under HHcy. Stimulation of contralateral whiskers elicited larger Ca2+transients in individual astrocytes of HHcy diet mice compared to control diet mice. However, evoked Ca2+signaling across astrocyte networks was impaired in HHcy mice. HHcy also was associated with increased activation of the Ca2+/calcineurin (CN) dependent transcription factor NFAT4, which has been linked previously to the reactive astrocyte phenotype and synapse dysfunction in amyloid and brain injury models. Targeting the NFAT inhibitor VIVIT to astrocytes, using adeno-associated virus (AAV) vectors, led to reduced GFAP promoter activity in HHcy diet mice, and improved functional hyperemia in arterioles and capillaries. VIVIT expression in astrocytes also preserved CA1 synaptic function and improved spontaneous alternation performance on the Y maze. Together, the results demonstrate that aberrant astrocyte signaling can impair the major functional properties of the neurovascular unit (i.e.cerebral vessel regulation and synaptic regulation) and may therefore represent a promising drug target for treating VCID and possibly other ADRDs.

Hippocampal glial inflammatory markers are differentially altered in a novel mouse model of perimenopausal cerebral amyloid angiopathy

“…Astrocytes form a critical component of both the neurovascular unit as well as the tripartite synapse, that are critical for maintaining cerebral function. and which show dysfunction in the hippocampus in models of cerebrovascular disease ( Sompol et al, 2023 ) and dementia ( Liu et al, 2018 ). Beyond neurovascular function, astrocytes are also involved in the clearance of Aβ ( Wyss-Coray et al, 2003 ; Kantarci et al, 2016 ; Davis et al, 2021 ), but may also contribute to Aβ production as well ( Frost and Li, 2017 ).…”

Astroglial activation: Current concepts and future directions

“…Beneficial actions in brain are found even when calcineurin/NFAT inhibition is limited to astrocytes, suggesting that reactive astrocytes play a causative role in pathophysiology and cognitive decline in AD. 58,59 Despite the indispensable role that astrocytes play in the neurovascular unit, the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology was explored in mice fed with a vitamin B deficient diet resulting in hyperhomocysteinemia (HHcy), cerebral vessel disease, and cognitive decline. Astrocyte-specific inhibition of the calcium-dependent transcription factor, NFAT, normalized cerebrovascular function in HHcy mice, ameliorated synaptic properties in brain slices, and stabilized cognition.…”

“…Drugs that target CN/NFAT activity including commercially available calcineurin inhibitors (e.g., tacrolimus), small chemical NFAT inhibitors (e.g., Q134R), or peptide‐based NFAT inhibitors improve neuronal viability and/or function in animal models exhibiting AD‐like pathology. Beneficial actions in brain are found even when calcineurin/NFAT inhibition is limited to astrocytes, suggesting that reactive astrocytes play a causative role in pathophysiology and cognitive decline in AD 58,59 …”

“…Beneficial actions in brain are found even when calcineurin/NFAT inhibition is limited to astrocytes, suggesting that reactive astrocytes play a causative role in pathophysiology and cognitive decline in AD. 58 , 59 …”

“…Astrocyte‐specific inhibition of the calcium‐dependent transcription factor, NFAT, normalized cerebrovascular function in HHcy mice, ameliorated synaptic properties in brain slices, and stabilized cognition. 58 …”