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

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.

The P2X7 Receptor, a Multifaceted Receptor in Alzheimer’s Disease

“…In contrast to the above, a recent study determining a polygenic risk score based on 12 P2X7 SNPs and 1 P2X4 SNP in a cohort of 902 subject controls and 328 AD patients did not provide evidence of an association between P2X7 and the risk of developing AD [39]. However, identifying specific single nucleotide polymorphisms (SNPs) is not easy due to the large number of P2X7 variants that can be associated with gain or loss of functions.…”

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“…Five genes ( TNFRSF13C, CXCL3, CXCL12, CCL4L1 , and CCL1 ) overlapped between the two sets and were associated with CSF AD biomarkers 187 . Expression of a pro‐inflammatory receptor (P2X purinoceptor 7) and two integrins (CD11b and CD11c) involved in phagocytosis on leukocytes was lower in A+ CU ADNI participants and associated with higher Aβ burden, more severe atrophy, and worse cognition 188 …”

“…187 Expression of a pro-inflammatory receptor (P2X purinoceptor 7) and two integrins (CD11b and CD11c) involved in phagocytosis on leukocytes was lower in A+ CU ADNI participants and associated with higher Aβ burden, more severe atrophy, and worse cognition. 188 In a UK Biobank study with validation in ADNI, two SNPs in two AD risk alleles involved in neuroinflammation, CLU and CD33, were associated with faster MCI to AD progression in the presence of Creactive protein (CRP), a marker of peripheral inflammation 189 (Figure S24 in supporting information). Elevated CRP was found only in APOE ε4 homozygotes and was associated with increased CSF p-tau181 and t-tau, and worse global cognition.…”

“… 187 Expression of a pro‐inflammatory receptor (P2X purinoceptor 7) and two integrins (CD11b and CD11c) involved in phagocytosis on leukocytes was lower in A+ CU ADNI participants and associated with higher Aβ burden, more severe atrophy, and worse cognition. 188 …”

Purinergic Signalling in Physiology and Pathophysiology

“…Using blood samples from people with Alzheimer's disease or mild cognitive impairment and from healthy individuals, Li et al [15] report in their original research article that amounts of cell-surface P2X7 receptors are decreased on leukocytes from people positive for beta-amyloid plaques. This was observed for classical, non-classical and intermediate monocytes, as well as neutrophils, natural killer cells, and B and T cells combined.…”