Loss of Pericyte Exacerbates Alzheimer's Disease‐Associated Retinal Pathology

ABSTRACT Background The retina, part of the central nervous system, reflects brain pathology. In Alzheimer's disease (AD), it shows changes like amyloid beta (Aβ) accumulation and vascular alterations. Pericytes modulate the glymphatic system, crucial for Aβ clearance, but their role in the ocular glymphatic system is unclear. This study explores pericytes' impact on the glymphatic system and AD‐related retinal pathology. Methods APP/PS1 mice, a model of progressive Aβ deposition, were crossed with Pdgfr‐β +/− mice, which exhibit pericyte dysfunction due to haploinsufficiency of platelet‐derived growth factor receptor β (Pdgfr‐β), generating four littermate genotypes: wild type, Pdgfr‐β +/− , APP/PS1 and APP/PS1:Pdgfr‐β +/− . Retinal pericytes were assessed by PDGFR‐β and NG 2 labelling, vascular complexity by OCTA and CD31 immunostaining and glymphatic‐related regulation by laminin‐211 and perivascular aquaporin‐4 (AQP‐4) expression. Retinal Aβ and p‐Tau pathology was evaluated by immunofluorescence. Retinal Aβ clearance was assessed in wild type and Pdgfr‐β +/− mice using intravitreal FAM–Aβ (1–42) injection followed by quantification of tracer efflux along the optic nerve to the deep cervical lymph nodes. Results Pdgfr‐β knockdown exacerbated retinal pericyte loss, leading to reduced laminin‐211 expression, disrupted perivascular AQP‐4 polarisation and impaired ocular glymphatic Aβ clearance. Consequently, this disruption is associated with increased Aβ and p‐Tau pathology, reduced vascular complexity and thinning of the retinal layers in APP/PS1 mice. Conclusions The loss of retinal pericytes is one of the major factors in retinal pathology associated with AD. It exacerbates Aβ and p‐Tau pathology and causes retinal vascular and structural damage by affecting the function of the ocular glymphatic system.