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Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease

Alzheimer’s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychologi...

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Autores principales: Li, Yihan, Huang, Xin, Fowler, Christopher, Lim, Yen Y., Laws, Simon M., Faux, Noel, Doecke, James D., Trounson, Brett, Pertile, Kelly, Rumble, Rebecca, Doré, Vincent, Villemagne, Victor L., Rowe, Christopher C., Wiley, James S., Maruff, Paul, Masters, Colin L., Gu, Ben J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322488/
https://www.ncbi.nlm.nih.gov/pubmed/35887215
http://dx.doi.org/10.3390/ijms23147867
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author Li, Yihan
Huang, Xin
Fowler, Christopher
Lim, Yen Y.
Laws, Simon M.
Faux, Noel
Doecke, James D.
Trounson, Brett
Pertile, Kelly
Rumble, Rebecca
Doré, Vincent
Villemagne, Victor L.
Rowe, Christopher C.
Wiley, James S.
Maruff, Paul
Masters, Colin L.
Gu, Ben J.
author_facet Li, Yihan
Huang, Xin
Fowler, Christopher
Lim, Yen Y.
Laws, Simon M.
Faux, Noel
Doecke, James D.
Trounson, Brett
Pertile, Kelly
Rumble, Rebecca
Doré, Vincent
Villemagne, Victor L.
Rowe, Christopher C.
Wiley, James S.
Maruff, Paul
Masters, Colin L.
Gu, Ben J.
author_sort Li, Yihan
collection PubMed
description Alzheimer’s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ −ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD.
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spelling pubmed-93224882022-07-27 Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease Li, Yihan Huang, Xin Fowler, Christopher Lim, Yen Y. Laws, Simon M. Faux, Noel Doecke, James D. Trounson, Brett Pertile, Kelly Rumble, Rebecca Doré, Vincent Villemagne, Victor L. Rowe, Christopher C. Wiley, James S. Maruff, Paul Masters, Colin L. Gu, Ben J. Int J Mol Sci Article Alzheimer’s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ −ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD. MDPI 2022-07-17 /pmc/articles/PMC9322488/ /pubmed/35887215 http://dx.doi.org/10.3390/ijms23147867 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Yihan
Huang, Xin
Fowler, Christopher
Lim, Yen Y.
Laws, Simon M.
Faux, Noel
Doecke, James D.
Trounson, Brett
Pertile, Kelly
Rumble, Rebecca
Doré, Vincent
Villemagne, Victor L.
Rowe, Christopher C.
Wiley, James S.
Maruff, Paul
Masters, Colin L.
Gu, Ben J.
Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease
title Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease
title_full Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease
title_fullStr Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease
title_full_unstemmed Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease
title_short Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease
title_sort identification of leukocyte surface p2x7 as a biomarker associated with alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322488/
https://www.ncbi.nlm.nih.gov/pubmed/35887215
http://dx.doi.org/10.3390/ijms23147867
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