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GNPS - The influence of APOE4 on the pTau interactome in sporadic Alzheimers disease

ABSTRACT: APOE4 is the major genetic risk factor for sporadic Alzheimers disease (AD). Although APOE4 is well known to promote Abeta pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n=5 APOE3 and n=5 APOE4), using a combination of anti-pTau PHF1 (pS396/pS404) immunoprecipitation and mass spectrometry. This proteomic approach was complemented by a neuropathological analysis of anti-pTau PHF1 and anti-Abeta 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n=11 APOE3 and n=10 APOE4). Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOE3 and APOE4 groups (FC over 1.50, IPPHF1 versus IPIgG ctrl). We identified 80 and 68 proteins as strong pTau interactors in APOE3 and APOE4 groups, respectively (SAINT score above 0.80; FDR under 5%). A total of 47/80 proteins were identified as strong pTau interactors only for APOE3 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as strong pTau interactors only for APOE4 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A comprehensive characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE4 cases. Our study supports an influence of APOE genotype on pTau subcellular location in the human brain. These results are consistent with a facilitation of pTau progression to Abeta-affected brain regions of APOE4 carriers, paving the way to the identification of potential new therapeutic targets. This entry contains the mass spectrometric raw files for the immune purifications.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Beatrix Ueberheide

PROVIDER: MSV000094757 | GNPS | Tue May 14 15:00:00 BST 2024

SECONDARY ACCESSION(S): PXD052263

REPOSITORIES: GNPS

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Project description:APOE4 is the major genetic risk factor for sporadic Alzheimers disease (AD). Although APOE4 is well known to promote Abeta pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n=5 APOE3 and n=5 APOE4), using a combination of anti-pTau PHF1 (pS396/pS404) immunoprecipitation and mass spectrometry. This proteomic approach was complemented by a neuropathological analysis of anti-pTau PHF1 and anti-Abeta 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n=11 APOE3 and n=10 APOE4). Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOE3 and APOE4 groups (FC over 1.50, IPPHF1 versus IPIgG ctrl). We identified 80 and 68 proteins as strong pTau interactors in APOE3 and APOE4 groups, respectively (SAINT score above 0.80; FDR under 5%). A total of 47/80 proteins were identified as strong pTau interactors only for APOE3 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as strong pTau interactors only for APOE4 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A comprehensive characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE4 cases. Our study supports an influence of APOE genotype on pTau subcellular location in the human brain. These results are consistent with a facilitation of pTau progression to Abeta-affected brain regions of APOE4 carriers, paving the way to the identification of potential new therapeutic targets. This entry contains the mass spectrometric raw files for the immune purifications.

Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.

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GNPS - The influence of APOE4 on the pTau interactome in sporadic Alzheimers disease

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