Identification of early pericyte loss and vascular amyloidosis in Alzheimer\u2019s disease retina

Haoshen Shi,Nazanin Mirzaei,David R Hinton,Alexander V Ljubimov,Maya Koronyo-Hamaoui,Carol A Miller,Keith L Black,Ernesto Barron,Yosef Koronyo,Anthony R Rodriguez,Julia Sheyn,Andrei A Kramerov,Oana M Dumitrascu,Altan Rentsendorj,Giovanna C Regis,Dieu-Trang Fuchs

doi:10.1007/s00401-020-02134-w

Abstract

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.

Highlights

Cerebral amyloid angiopathy (CAA) is a complex pathological feature found in over 85% of Alzheimer’s disease (AD) patients involving deposition of amyloid β-protein (Aβ) in blood vessels and other vascular abnormalities [5, 78]
Our findings indicate that along with the substantial increase in retinal vascular amyloidosis in postmortem retinas from AD patients, there was an early and progressive loss of retinal vascular platelet-derived growth factor receptor-β (PDGFRβ) in pericytes and vascular smooth muscle cells (vSMCs) that associated with AD pathology in the brain
To exclusively investigate the extent of retinal microvascular amyloidosis and possible pericyte degeneration in AD without interference from other retinal tissues, we enzymatically digested retinas, preserved solely the vascular network [51, 77], and subsequently conducted fluorescent immunostaining for blood vessels, PDGFRβ, and different types of Aβ (Fig. 1; extended data in Supplementary Fig. 2, online resource)

Summary

Introduction

Cerebral amyloid angiopathy (CAA) is a complex pathological feature found in over 85% of Alzheimer’s disease (AD) patients involving deposition of amyloid β-protein (Aβ) in blood vessels and other vascular abnormalities [5, 78]. Brain vascular and perivascular Aβ deposits have been associated with reduced blood and lymphatic flow [8, 54], impaired gliovascular unit [43], as well as altered vessel diameter and accessibility of peripheral immune cells [49] These combined processes may lead to reduced Aβ clearance rate, heightened inflammation, and eventually neurodegeneration. Pericyte loss, as assessed by pericyte marker platelet-derived growth factor receptor-β (PDGFRβ) in BBB, was tightly associated with functional breakdown of this barrier [61] This cell surface receptor is expressed by vascular smooth muscle cells (vSMCs), which are present in all types of blood vessels except for capillaries and pericytic venules [71]. Studies in rodents have shown that the loss of PDGFRβ expression alone leads to a decrease in pericyte and vSMC numbers [38] and damaged brain vasculature [61]

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