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Studies in animal models have characterized the local immune response to disease-specific proteins in AD and ADRD, but due to the complexity of disease processes and the co-existence of multiple protein pathologies in human donor brains, the precise role of immune processes in ND is far from understood. To better characterize the interplay between different extracellular and intracellular protein pathologies and the brain\u2019s intrinsic immune system in ND, we set out to comprehensively profile the local immune response in postmortem brain samples of individuals with \u201cpure\u201d beta-Amyloid and tau pathology (AD), \u201cpure\u201d \u03b1-Synuclein pathology in Lewy body diseases (LBD), as well as cases with Alzheimer\u2019s disease neuropathological changes (ADNC) and Lewy body pathology (MIX). Combining immunohistochemical profiling of microglia and digital image analysis, along with deep immunophenotyping using gene expression profiling on the NanoString nCounter\u00ae platform and digital spatial profiling on the NanoString GeoMx\u00ae platform we identified a robust immune activation signature in AD brain samples. This signature is maintained in persons with mixed pathologies, irrespective of co-existence of AD pathology and Lewy body (LB) pathology, while LBD brain samples with \u201cpure\u201d LB pathology exhibit an attenuated and distinct immune signature. Our studies highlight disease- and brain region-specific immune response profiles to intracellular and extracellular protein pathologies and further underscore the complexity of neuroimmune interactions in ND.<\/jats:p>","DOI":"10.1186\/s40478-024-01770-7","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T05:02:01Z","timestamp":1712293321000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Disease and brain region specific immune response profiles in neurodegenerative diseases with pure and mixed protein pathologies"],"prefix":"10.1186","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9824-2064","authenticated-orcid":false,"given":"Tim","family":"Bathe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela P.","family":"Hery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A. 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