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

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posted on 10.05.2021, 09:36 by Ren Ding, Yoshiki Hase, Kamar E Ameen-Ali, Michael Ndung'u, William Stevenson, Joseph Barsby, Ryan Gourlay, Tolulope Akinyemi, Rufus Akinyemi, Maiko T Uemura, Tuomo Polvikoski, Elizabeta Mukaetova-Ladinska, Masafumi Ihara, Raj N Kalaria
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.

Funding

Our work is supported by grants from the UK Medical Research Council (MRC, G0500247), Newcastle Centre for Brain Aging and Vitality (BBSRC, EPSRC, ESRC and MRC, LLHW) and Alzheimer’s Research (ARUK; Award PG2013‐22).

History

Citation

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. (2020), Loss of capillary pericytes and the blood–brain barrier in white matter in poststroke and vascular dementias and Alzheimer’s disease. Brain Pathol., 30: 1087-1101. https://doi.org/10.1111/bpa.12888

Version

VoR (Version of Record)

Published in

Brain Pathology

Volume

30

Pagination

1087-1101

Publisher

Wiley Open Access [Commercial Publisher] International Society of Neuropathology [Associate Organisation]

issn

1015-6305

eissn

1750-3639

Acceptance date

14/08/2020

Copyright date

2020

Available date

10/05/2021

Spatial coverage

Switzerland

Language

eng