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

Yihan Li, Xin Huang, Christopher Fowler, Yen Y. Lim, Simon M. Laws, Noel Faux, James D. Doecke, Brett Trounson, Kelly Pertile, Rebecca Rumble, Vincent Doré, Victor L. Villemagne, Christopher C. Rowe, James S. Wiley, Paul Maruff, Colin L. Masters, Ben J. Gu

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Abstract

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.

Original languageEnglish
Article number7867
Number of pages22
JournalInternational Journal of Molecular Sciences
Volume23
Issue number14
DOIs
Publication statusPublished - Jul 2022

Keywords

  • brain atrophy
  • CSF Aβ
  • CSF P-tau181P
  • CSF T-tau
  • episodic memory
  • myeloid cells
  • purinergic receptors
  • the Preclinical Alzheimer’s Cognitive Composite (PACC)

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