Loss of capillary pericytes and the blood–brain barrier in white matter in poststroke and vascular dementias and Alzheimer’s disease

Abstract

White matter (WM) disease is associated with disruption of the gliovascular unit, which involves breach of the blood–brain barrier (BBB). We quantified pericytes as components of the gliovascular unit and assessed their status in vascular and other common dementias. Immunohistochemical and immunofluorescent methods were developed to assess the distribution and quantification of pericytes connected to the frontal lobe WM capillaries. Pericytes with a nucleus were identified by collagen 4 (COL4) and platelet‐derived growth factor receptor‐β (PDGFR‐β) antibodies with further verification using PDGFR‐β‐specific ELISA. We evaluated a total of 124 post‐mortem brains from subjects with post‐stroke dementia (PSD), vascular dementia (VaD), Alzheimer’s disease (AD), AD‐VaD (Mixed) and post‐stroke non‐demented (PSND) stroke survivors as well as normal aging controls. COL4 and PDGFR‐β reactive pericytes adopted the characteristic “crescent” or nodule‐like shapes around capillary walls. We estimated densities of pericyte somata to be 225 ±38 and 200 ±13 (SEM) per COL4 mm2 area or 2.0 ± 0.1 and 1.7 ± 0.1 per mm capillary length in young and older aging controls. Remarkably, WM pericytes were reduced by ~35%–45% in the frontal lobe of PSD, VaD, Mixed and AD subjects compared to PSND and controls subjects (P < 0.001). We also found pericyte numbers were correlated with PDGFR‐β reactivity in the WM. Our results first demonstrate a reliable method to quantify COL4‐positive pericytes and then, indicate that deep WM pericytes are decreased across different dementias including PSD, VaD, Mixed and AD. Our findings suggest that downregulation of pericytes is associated with the disruption of the BBB in the deep WM in several aging‐related dementias.

Cognitive impact of COVID-19: looking beyond the short term

“…Studies of microvascular endothelial cell monolayers [96,97], human APP transgenic mouse models [98], and on human post-mortem brain tissue [99] indicate that Aβ peptides also impair BBB function, in part by reducing expression of tight junction proteins. Pericyte degeneration in AD is associated with BBB breakdown [100][101][102]. Pericyte loss accelerates Aβ pathology and induces tau pathology and cognitive decline in human APP mice [103].…”

Reduction of Pericyte Coverage Leads to Blood-Brain Barrier Dysfunction Via Endothelial Transcytosis Following Chronic Cerebral Hypoperfusion

“…Ding et al nds capillary pericyte loss is the common characteristic of these patients [44]. Ding et al ndings indicate that capillary pericyte loss is the structural basis of BBB dysfunction in the aging-related dementias [44].…”

“…This rat model is known to be a model of human sporadic CSVD [43]. On the other hand, Ding et al analyzed frontal WM post-mortem brains from 124 subjects with post-stroke dementia (PSD), VD, AD, AD-VD (Mixed), and poststroke non-demented (PSND) stroke survivors as well as normal ageing controls [44]. Ding et al nds capillary pericyte loss is the common characteristic of these patients [44].…”

“…On the other hand, Ding et al analyzed frontal WM post-mortem brains from 124 subjects with post-stroke dementia (PSD), VD, AD, AD-VD (Mixed), and poststroke non-demented (PSND) stroke survivors as well as normal ageing controls [44]. Ding et al nds capillary pericyte loss is the common characteristic of these patients [44]. Ding et al ndings indicate that capillary pericyte loss is the structural basis of BBB dysfunction in the aging-related dementias [44].…”

“…Ding et al nds capillary pericyte loss is the common characteristic of these patients [44]. Ding et al ndings indicate that capillary pericyte loss is the structural basis of BBB dysfunction in the aging-related dementias [44]. Furthermore, Bell et al also nds pericyte control key neurovascular function in the adult brain and during normal aging [45].…”