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SHIP2, encoded by <jats:italic>INPPL1<\/jats:italic>, is taking part in the signalling and interactome of several growth factor receptors, such as the EGFR. While <jats:italic>INPPL1<\/jats:italic> has been identified as one of the most significant genes whose RNA expression correlates with cognitive decline, the potential alteration of SHIP2 expression and localization during the progression of AD remains largely unknown. Here we report that gene expression of both <jats:italic>EGFR<\/jats:italic> and <jats:italic>INPPL1<\/jats:italic> was upregulated in AD brains. SHIP2 immunoreactivity was predominantly detected in plaque-associated astrocytes and dystrophic neurites and its increase was correlated with amyloid load in the brain of human AD and of 5xFAD transgenic mouse model of AD. While mRNA of <jats:italic>INPPL1<\/jats:italic> was increased in AD, SHIP2 protein undergoes a significant solubility change being depleted from the soluble fraction of AD brain homogenates and co-enriched with EGFR in the insoluble fraction. Using FRET-based flow cytometry biosensor assay for tau-tau interaction, overexpression of SHIP2 significantly increased the FRET signal while siRNA-mediated downexpression of SHIP2 significantly decreased FRET signal. Genetic association analyses suggest that some variants in <jats:italic>INPPL1<\/jats:italic> locus are associated with the level of CSF pTau. Our data support the hypothesis that SHIP2 is an intermediate key player of EGFR and AD pathology linking amyloid and tau pathologies in human AD.<\/jats:p>","DOI":"10.1007\/s00401-024-02745-7","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T11:45:28Z","timestamp":1717501528000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer\u2019s disease pathology progression"],"prefix":"10.1007","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-175X","authenticated-orcid":false,"given":"Kunie","family":"Ando","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahri","family":"K\u00fc\u00e7\u00fckali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Doeraene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siranjeevi","family":"Nagaraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia Maria","family":"Antonelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May","family":"Thazin Htut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehra","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea-Claudia","family":"Kosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Lopez-Guitierrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Quintanilla-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Aydin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Raquel","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salwa","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Turbant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Schurmans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristel","family":"Sleegers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Erneux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Brion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karelle","family":"Leroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Brain Bank NeuroCEB Neuropathology Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,4]]},"reference":[{"key":"2745_CR1","doi-asserted-by":"publisher","first-page":"160089","DOI":"10.1038\/sdata.2016.89","volume":"3","author":"M Allen","year":"2016","unstructured":"Allen M, Carrasquillo MM, Funk C, Heavner BD, Zou F, Younkin CS et al (2016) Human whole genome genotype and transcriptome data for Alzheimer\u2019s and other neurodegenerative diseases. 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