The pTau interactome in sporadic Alzheimer’s disease across APOE genotypes

Abstract

AbstractBackgroundAPOE polymorphism is the major genetic risk factor for sporadic Alzheimer’s disease (AD), characterized by the abnormal accumulation of β‐amyloid (Aβ) and phosphorylated Tau (pTau). Although the various ApoE isoforms are known mostly to differentially modulate Aβ aggregation and clearance, recent data support an influence of APOE genotype on pTau accumulation, which correlates better with AD symptom progression. The exact effects of ApoE isoforms on pTau metabolism, however, remain unclear.MethodThe localized proteomic methods developed in our laboratory, on post‐mortem human brain, are an ideal strategy to elucidate these aspects de novo. Co‐immunopurifications (IP) against pTau pSer396/pSer404 (PHF1) from frozen frontal cortex were combined with mass spectrometry to map out, for the first time, the pTau interactome across APOE genotypes in 10 sporadic AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4).ResultA total of 1130 and 1330 proteins were enriched in the IPPHF1 samples of the APOEε3/ε3 and APOEε4/ε4 groups (FC ≥ 1.50, IPPHF1 vs. IPIgG ctrl) and represented respectively 62% and 70% of the proteins previously identified as bona fide pTau interactors, validating our approach (Drummond et al., 2020). We identified 184 and 176 proteins as bona fide pTau interactors in the APOEε3/ε3 and APOEε4/ε4 groups (SAINT scores ≥ 0.65). Only 79 pTau interactors were common to both APOE groups and were mostly involved in proteostasis pathways (ubiquitin‐proteasome system, RNA metabolism, endo‐lysosomal trafficking). The pTau interactome of the APOEε3/ε3 group contained 17 proteins upregulated in APOEε3/ε3 cases (FC ≥ 1.50, IPPHF1 (APOEε3/ε3) vs. IPPHF1 (APOEε4/ε4))), a large majority of which being involved in RNA binding, processing or splicing (13/17 proteins, STRING analysis). The pTau interactome of the APOEε4/ε4 group contained 33 proteins upregulated in APOEε4/ε4 cases (FC ≥ 1.50, IPPHF1 (APOEε4/ε4) vs. IPPHF1 (APOEε3/ε3))), most of them being involved in synaptic transmission pathways (16/33 proteins, STRING analysis).ConclusionOur proteomic data highlighted an influence of the APOE polymorphism on pTau metabolism. These results will be validated in the human brain using histological and biochemical methods, paving the way to the identification of new therapeutic targets for AD.