Pericyte loss contributes to impaired venous drainage in a mouse model with Alzheimer’s disease-like pathology

The loss of brain pericytes occurs during aging and has been linked to vessel regression through changes in capillary flow patterns. However, the consequence of pericyte loss remains poorly understood in conditions involving amyloid-β burden. We performed in vivo two-photon imaging in the Tg-SwDI mouse model of Type-1 cerebral amyloid angiopathy and other aspects of Alzheimer’s disease-like pathology to examine basal pericyte coverage and the effect of optically-induced pericyte loss. We find that spontaneous pericyte loss occurs preferentially on peri-venous capillaries in the somatosensory cortex of Tg-SwDI mice. Optically-induced pericyte ablation revealed slower structural remodeling of neighboring pericytes in Tg-SwDI mice, with the largest deficits seen in the peri-venous zone. Spontaneous pericyte loss in Tg-SwDI mice was associated with longer and more tortuous peri-venous capillaries indicative of vessel rarefaction. Mimicking peri-venous capillary regression by targeted optical ablation in wild-type mice reduced downstream blood flow by ~50-75%, while creating abnormal capillary flow heterogeneity upstream. These results suggest a selective vulnerability of the peri-venous zone in Type-1 cerebral amyloid angiopathy, and link pericyte loss to capillary rarefaction that may impair cerebral perfusion.