Pericyte loss and deficient vascular
platelet-derived growth factor receptor-β (PDGFRβ) 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 β-
protein (Aβ) 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 Aβ 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 PDGFRβ in
mild cognitive impairment (MCI) and AD compared to cognitively normal controls.
Retinal PDGFRβ loss significantly associated with increased
retinal vascular Aβ40 and Aβ42 burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFRβ and Aβ40 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 Aβ burden,
cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFRβ loss accompanying increased vascular
amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and
therapy.