Chemogenetic modulation of CNS pericytes: Impact on pericyte Ca2+ dynamics, CBF, BBB, and Alzheimer's disease progression in mice.

Brain capillary pericytes control cerebral blood flow (CBF) and maintain the integrity of the blood-brain barrier (BBB). Amyloid-evoked pericyte constriction may contribute to the CBF reduction in Alzheimer's disease (AD) initiation and subsequent cognitive impairments. Therapeutic approaches to specifically manipulating pericytes are still lacking. Using in vivo calcium (Ca2+) imaging, chemogenetics, and blood flow imaging, we demonstrate that chemogenetic activation of pericyte Gi signaling significantly increases BBB permeability, elevates cortical pericyte Ca2+ transient peak amplitude and frequency, and reduces local red blood cell velocity (RBCv; a proxy of capillary CBF) in adult wild-type (WT) mice. In contrast, activating pericyte Gq signaling in WT mice does not notably affect BBB permeability or cortical pericyte Ca2+ transients but leads to a significant increase in local RBCv. Chronic activation of pericyte Gi signaling for 30 days in adult 5xFAD mice exacerbated Aβ accumulation, enhanced microglial activation, and worsened working and spatial memory and learning deficits. Conversely, chronic activation of Gq signaling in adult 5xFAD mice reduced Aβ deposition, decreased microglial activation, and improved spatial learning. These findings suggest that systemic inhibition of CNS pericytes could be a promising therapeutic strategy for slowing AD progression by preserving BBB integrity, increasing CBF, and reducing neuroinflammation.