Targeting Reactive Astrocytes in Vascular Dementia: Investigation of Neuronal-Astrocyte-Vascular Interactions

Abstract

Historically known as neuronal support cells, astrocytes are now widely studied for their close structural and functional interactions with multiple neural cell types and cerebral vessels where they maintain an ideal environment for optimized brain function. Under pathological conditions, astrocytes become reactive and lose key protective functions. In this commentary, we discuss our recent work in The Journal of Neuroscience (Sompol et al., 2023) that showed Ca2+ dysregulation in reactive astrocytes, as well as hyperactivation of the Ca2+-dependent protein phosphatase calcineurin (CN) and the Nuclear Factor of Activated T Cells (NFATs), in a diet-induced hyperhomocystienemia (HHcy) mouse model of Vascular Contributions to Cognitive Impairment and Dementia (VCID). Intravital multiphoton imaging coupled with whisker stimulation was used to explore astrocyte Ca2+ signaling and neurovascular function under active phase, fully awake conditions. Interestingly, evoked Ca2+ transients in individual astrocytes were greater, even though intercorrelated Ca2+ signaling across networks of astrocytes was impaired in HHcy mice. Blockade of astrocytic CN/NFAT reduced signs of astrocyte reactivity, normalized cerebrovascular function, and improved hippocampal synaptic strength and hippocampal dependent cognition in HHcy mice, revealing a previously unrecognized deficit regarding neuron-astrocyte-vascular interactions. These findings strongly support the use of astrocyte targeting strategies to mitigate pathophysiological changes associated with VCID and other Alzheimer's-related dementias.

Keywords: Alzheimer’s disease; Vascular dementia; astrocyte; neurovascular function; synapse.

Figure 1.

Schematic illustrates complexity of astrocyte interaction with brain cells and the cerebral vasculature under physiological and systemic HHcy conditions. (A) Astrocytes interact with adjacent brain cells and maintain physiological environment for optimized synaptic transmission, cerebral blood flow and brain function. These processes could be regulated, in part, by Ca2+ signaling across the astrocyte syncytium. (B) Astrocyte reactivity is evidenced by dysregulation of Ca2+ signaling and hyperactivation of the CN/NFAT pathway. Abnormal astrocyte networking and astrocyte related impairments in cerebrovascular hyperemic responses are observed. These findings are correlated with neuroinflammation, deficits of synaptic transmission and brain function. Targeting reactive astrocytes by expressing the VIVIT peptide, a blocker of CN/NFAT signaling, provides a promising neuro- and cerebrovascular protection strategy for VCID, AD, and other ADRDs. (Figure was generated and modified by Biorender.com)