Disrupted Calcium Dynamics in Reactive Astrocytes Occur with Endfeet-Arteriole Decoupling in an Amyloid Mouse Model of Alzheimer's Disease

Abstract

While cerebrovascular dysfunction and reactive astrocytosis are extensively characterized hallmarks of Alzheimers disease (AD) and related dementias, the dynamic relationship between reactive astrocytes and cerebral vessels remains poorly understood. Here, we used jGCaMP8f and two photon microscopy to investigate Ca2+ signaling in multiple astrocyte subcompartments, concurrent with changes in cerebral arteriole activity, in fully awake eight-month-old male and female 5xFAD mice, a model for AD-like pathology, and wild-type (WT) littermates. In the absence of movement, spontaneous Ca2+ transients in barrel cortex occurred more frequently in astrocyte somata, processes, and perivascular regions of 5xFAD mice. However, evoked arteriole dilations (in response to air puff stimulation of contralateral whiskers) and concurrent Ca2+ transients across astrocyte compartments were reduced in 5xFAD mice relative to WTs. Synchronous activity within multi-cell astrocyte networks was also impaired in the 5xFAD group. Using a custom application to assess functional coupling between astrocyte endfeet and immediately adjacent arteriole segments, we detected deficits in Ca2+ response probability in 5xFAD mice. Moreover, endfeet Ca2+ transients following arteriole dilations exhibited a slower onset, reduced amplitude, and lacked relative proportionality to vasomotive activity compared to WTs. The results reveal nuanced alterations in 5xFAD reactive astrocytes highlighted by impaired signaling fidelity between astrocyte endfeet and cerebral arterioles. The results have important implications for the mechanistic underpinnings of brain hypometabolism and the disruption of neurophysiological communication found in AD and other neurodegenerative conditions. Significance StatementAstrocytes are an essential component of the neurovascular unit. Chronically reactive astrocyte phenotypes are mechanistically linked to deleterious features of Alzheimers disease (AD) including impaired cerebral blood flow, hypometabolism, and synapse dysfunction/loss. Here, we show that reactive astrocytes in a fully awake mouse model of AD-like amyloid pathology are spontaneously hyperactive, exhibit impaired functional connectivity, and respond to dilations in immediately adjacent arterioles with poor fidelity. The results reveal a key point of communication breakdown between the brain and the cerebrovasculature.