TY - JOUR
T1 - Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease
AU - Li, Yihan
AU - Huang, Xin
AU - Fowler, Christopher
AU - Lim, Yen Y.
AU - Laws, Simon M.
AU - Faux, Noel
AU - Doecke, James D.
AU - Trounson, Brett
AU - Pertile, Kelly
AU - Rumble, Rebecca
AU - Doré, Vincent
AU - Villemagne, Victor L.
AU - Rowe, Christopher C.
AU - Wiley, James S.
AU - Maruff, Paul
AU - Masters, Colin L.
AU - Gu, Ben J.
N1 - Funding Information:
This research was funded by ARC Future Fellowship (to B.G., FT120100581), NHMRC Project Grants (1048082, 1061419, 1120095, and 110178 to B.G.), the Ministry of Science and Technology of China (program grant No. SQ2018YFC200022 to B.G.), the Bethlehem Griffiths Research Foundation Grant (BGRF1901 to X.H.), and the Victorian Government’s Operational Infrastructure Support Grant to the Florey Institute.
Publisher Copyright:
© 2022 by the authors.
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - brain atrophy
KW - CSF Aβ
KW - CSF P-tau181P
KW - CSF T-tau
KW - episodic memory
KW - myeloid cells
KW - purinergic receptors
KW - the Preclinical Alzheimer’s Cognitive Composite (PACC)
UR - http://www.scopus.com/inward/record.url?scp=85135116083&partnerID=8YFLogxK
U2 - 10.3390/ijms23147867
DO - 10.3390/ijms23147867
M3 - Article
C2 - 35887215
AN - SCOPUS:85135116083
SN - 1422-0067
VL - 23
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 14
M1 - 7867
ER -