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We have identified previously unreported mutations in colony stimulating factor\u20101 receptor (\n                    <jats:italic>CSF\u20101R<\/jats:italic>\n                    ) in an ultra\u2010rare autosomal dominant condition termed adult\u2010onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP). Cerebrovascular pathologies such as cerebral amyloid angiopathy (CAA) and perivascular p\u2010Tau were some of the primary neuropathological features of this condition. We have identified two families with different dominant acting alleles with variants located in the kinase region of the\n                    <jats:italic>CSF\u20101R<\/jats:italic>\n                    gene, which confer a lack of kinase activity and signalling. The protein product of this gene acts as the receptor for 2 cognate ligands, namely colony stimulating factor\u20101 (CSF\u20101) and interleukin\u201034 (IL\u201034). Here, we show that depletion in CSF\u20101R signalling induces BBB disruption and decreases the phagocytic capacity of peripheral macrophages but not microglia. CSF\u20101R signalling appears to be critical for macrophage and microglial activation, and macrophage localisation to amyloid appears reduced following the induction of\n                    <jats:italic>Csf\u20101r<\/jats:italic>\n                    heterozygosity in macrophages. Finally, we show that endothelial\/microglial crosstalk and concomitant attenuation of CSF\u20101R signalling causes re\u2010modelling of BBB\u2010associated tight junctions and suggest that regulating BBB integrity and systemic macrophage recruitment to the brain may be therapeutically relevant in ALSP and other Alzheimer\u2019s\u2010like dementias.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202012889","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T17:14:57Z","timestamp":1608657297000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Attenuated CSF\u20101R signalling drives cerebrovascular pathology"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8735-2225","authenticated-orcid":false,"given":"Conor","family":"Delaney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Farrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin P","family":"Doherty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiva","family":"Brennan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eoin","family":"O\u2019Keeffe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Greene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieva","family":"Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eoin","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niamh","family":"Birmingham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Hickey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Cronin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savvas N","family":"Savvides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6294-9380","authenticated-orcid":false,"given":"Sarah L","family":"Doyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3325-240X","authenticated-orcid":false,"given":"Matthew","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,22]]},"reference":[{"key":"BFEMMM202012889_CR1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jocn.2017.10.060","volume":"48","author":"SJ Adams","year":"2018","unstructured":"Adams SJ, Kirk A, Auer RN (2018) Adult\u2010onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): Integrating the literature on hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). 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