Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina

Pericyte loss and deficient vascular platelet-derived growth factor receptor-beta (PDGFR beta) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid beta-protein (A beta) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant A beta deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFR beta in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFR beta loss significantly associated with increased retinal vascular A beta(40) and A beta(42) burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFR beta and A beta(40) levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral A beta burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFR beta loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.