Loss of capillary pericytes and the blood-brain barrier in white matter in post-stroke and vascular dementias and Alzheimer's disease

Ding, R. et al. (2020) Loss of capillary pericytes and the blood-brain barrier in white matter in post-stroke and vascular dementias and Alzheimer's disease. Brain Pathology, 30(6), pp. 1087-1101. (doi: 10.1111/bpa.12888) (PMID:32705757)

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 ageing 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 ageing controls. Remarkably, WM pericytes were reduced by ~35‐45 percent 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 down regulation of pericytes is associated with the disruption of the BBB in the deep WM in several ageing‐related dementias.

• Item Type: Articles
• Additional Information: Our work is supported by grants from the UK Medical Research Council (MRC, G0500247), Newcastle Centre for Brain Ageing and Vitality (BBSRC, EPSRC, ESRC and MRC, LLHW), and Alzheimer’s Research (ARUK; Award PG2013-22). Tissue for this study was collected by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK MRC (G0400074), by the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and by a grant from the Alzheimer’s Society and ARUK as part of the Brains for Dementia Research Project.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ameen-Ali, Dr Kamar
• Authors: Ding, R., Hase, Y., Ameen-Ali, K. E., Ndung'u, M., Stevenson, W., Barsby, J., Gourlay, R., Akinyemi, T., Akinyemi, R., Uemura, M.T., Polvikoski, T., Mukaetova-Ladinska, E., Ihara, M., and Kalaria, R.N.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Brain Pathology
• Publisher: Wiley
• ISSN: 1015-6305
• ISSN (Online): 1750-3639
• Published Online: 23 July 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Brain Pathology 30(6): 1087-1101
• Publisher Policy: Reproduced under a Creative Commons License