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Published in: Alzheimer's Research & Therapy 1/2019

Open Access 01-12-2019 | Alzheimer's Disease | Research

CSF evidence of pericyte damage in Alzheimer’s disease is associated with markers of blood-brain barrier dysfunction and disease pathology

Authors: J. S. Miners, P. G. Kehoe, S. Love, H. Zetterberg, K. Blennow

Published in: Alzheimer's Research & Therapy | Issue 1/2019

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Abstract

Background

We aimed to assess the relationship between levels of a cerebrospinal fluid (CSF) marker of pericyte damage, soluble platelet-derived growth factor receptor β (sPDGFRβ) and CSF markers of blood-brain barrier (BBB) integrity (CSF albumin and CSF/serum albumin ratio) and disease pathology (reduced CSF Aβ42 and elevated CSF total and phosphorylated tau) in Alzheimer’s disease (AD).

Methods

sPDGFRβ and albumin were measured by sandwich ELISA in ante-mortem CSF from 39 AD and 39 age-matched controls that were grouped according to their biomarker profile (i.e. AD cases t-tau > 400 pg/mL, p-tau > 60 pg/mL and Aβ42 < 550 pg/mL). sPDGFRβ was also measured in matched serum and CSF samples (n = 23) in a separate neurologically normal group for which the CSF/serum albumin ratio had been determined.

Results

CSF sPDGFRβ level was significantly increased in AD (p = 0.0038) and correlated positively with albumin (r = 0.45, p = 0.007), total tau (r = 0.50, p = 0.0017) and phosphorylated tau (r = 0.41, p = 0.013) in AD but not in controls. CSF sPDGFRβ did not correlate with Aβ42. Serum and CSF sPDGFRβ were positively correlated (r = 0.547, p = 0.0085) in the independent neurologically normal CSF/serum matched samples.

Conclusions

We provide further evidence of an association between pericyte injury and BBB breakdown in AD and novel evidence that a CSF marker of pericyte injury is related to the severity of AD pathology.
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Literature
1.
go back to reference Love S, Miners JS. Cerebrovascular disease in ageing and Alzheimer’s disease. Acta Neuropathol. 2016;131(5):645–58.CrossRef Love S, Miners JS. Cerebrovascular disease in ageing and Alzheimer’s disease. Acta Neuropathol. 2016;131(5):645–58.CrossRef
2.
go back to reference Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci. 2018;21(10):1318–31.CrossRef Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci. 2018;21(10):1318–31.CrossRef
3.
go back to reference Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab. 2016;36(1):216–27.CrossRef Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab. 2016;36(1):216–27.CrossRef
4.
go back to reference Miners JS, Schulz I, Love S. Differing associations between Abeta accumulation, hypoperfusion, blood-brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer’s disease. J Cereb Blood Flow Metab. 2018;38(1):103–15.CrossRef Miners JS, Schulz I, Love S. Differing associations between Abeta accumulation, hypoperfusion, blood-brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer’s disease. J Cereb Blood Flow Metab. 2018;38(1):103–15.CrossRef
5.
go back to reference Sagare AP, Sweeney MD, Makshanoff J, Zlokovic BV. Shedding of soluble platelet-derived growth factor receptor-beta from human brain pericytes. Neurosci Lett. 2015;607:97–101.CrossRef Sagare AP, Sweeney MD, Makshanoff J, Zlokovic BV. Shedding of soluble platelet-derived growth factor receptor-beta from human brain pericytes. Neurosci Lett. 2015;607:97–101.CrossRef
6.
go back to reference Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270–6.CrossRef Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270–6.CrossRef
7.
go back to reference Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85(2):296–302.CrossRef Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85(2):296–302.CrossRef
8.
go back to reference Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun. 2013;4:2932.CrossRef Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun. 2013;4:2932.CrossRef
9.
go back to reference Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5(3):228–34.CrossRef Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5(3):228–34.CrossRef
10.
go back to reference Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer’s disease. Brain Pathol. 2013;23(3):303–10.CrossRef Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer’s disease. Brain Pathol. 2013;23(3):303–10.CrossRef
11.
go back to reference Nikolakopoulou AM, Zhao Z, Montagne A, Zlokovic BV. Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-beta signaling. PLoS One. 2017;12(4):e0176225.CrossRef Nikolakopoulou AM, Zhao Z, Montagne A, Zlokovic BV. Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-beta signaling. PLoS One. 2017;12(4):e0176225.CrossRef
12.
go back to reference Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Perez JM, Evans AC. Alzheimer’s disease neuroimaging I. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat Commun. 2016;7:11934.CrossRef Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Perez JM, Evans AC. Alzheimer’s disease neuroimaging I. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat Commun. 2016;7:11934.CrossRef
13.
go back to reference Verbeek MM, de Waal RM, Schipper JJ, Van Nostrand WE. Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J Neurochem. 1997;68(3):1135–41.CrossRef Verbeek MM, de Waal RM, Schipper JJ, Van Nostrand WE. Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J Neurochem. 1997;68(3):1135–41.CrossRef
14.
go back to reference Verbeek MM, Van Nostrand WE, Otte-Holler I, Wesseling P, De Waal RM. Amyloid-beta-induced degeneration of human brain pericytes is dependent on the apolipoprotein E genotype. Ann N Y Acad Sci. 2000;903:187–99.CrossRef Verbeek MM, Van Nostrand WE, Otte-Holler I, Wesseling P, De Waal RM. Amyloid-beta-induced degeneration of human brain pericytes is dependent on the apolipoprotein E genotype. Ann N Y Acad Sci. 2000;903:187–99.CrossRef
15.
go back to reference Schultz N, Brannstrom K, Byman E, Moussaud S, Nielsen HM, Netherlands Brain B, et al. Amyloid-beta 1-40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro. Aging Cell. 2018;17(3):e12728.CrossRef Schultz N, Brannstrom K, Byman E, Moussaud S, Nielsen HM, Netherlands Brain B, et al. Amyloid-beta 1-40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro. Aging Cell. 2018;17(3):e12728.CrossRef
16.
go back to reference Liu Q, Radwanski R, Babadjouni R, Patel A, Hodis DM, Baumbacher P, et al. Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood-brain barrier permeability in the corpus callosum. J Cereb Blood Flow Metab. 2019;39(2):240–50.CrossRef Liu Q, Radwanski R, Babadjouni R, Patel A, Hodis DM, Baumbacher P, et al. Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood-brain barrier permeability in the corpus callosum. J Cereb Blood Flow Metab. 2019;39(2):240–50.CrossRef
17.
go back to reference Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, et al. Vascular dysfunction-the disregarded partner of Alzheimer’s disease. Alzheimers Dement. 2019;15(1):158–67.CrossRef Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, et al. Vascular dysfunction-the disregarded partner of Alzheimer’s disease. Alzheimers Dement. 2019;15(1):158–67.CrossRef
Metadata
Title
CSF evidence of pericyte damage in Alzheimer’s disease is associated with markers of blood-brain barrier dysfunction and disease pathology
Authors
J. S. Miners
P. G. Kehoe
S. Love
H. Zetterberg
K. Blennow
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2019
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-019-0534-8

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