
Attenuated CSF‐1R signalling drives cerebrovascular pathology
Author(s) -
Delaney Conor,
Farrell Michael,
Doherty Colin P,
Brennan Kiva,
O’Keeffe Eoin,
Greene Chris,
Byrne Kieva,
Kelly Eoin,
Birmingham Niamh,
Hickey Paula,
Cronin Simon,
Savvides Savvas N,
Doyle Sarah L,
Campbell Matthew
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012889
Subject(s) - trem2 , cerebral amyloid angiopathy , microglia , biology , pathology , macrophage colony stimulating factor , blood–brain barrier , immunology , microbiology and biotechnology , neuroscience , macrophage , medicine , central nervous system , inflammation , disease , dementia , genetics , in vitro
Cerebrovascular pathologies occur in up to 80% of cases of Alzheimer's disease; however, the underlying mechanisms that lead to perivascular pathology and accompanying blood–brain barrier (BBB) disruption are still not fully understood. We have identified previously unreported mutations in colony stimulating factor‐1 receptor ( CSF‐1R ) in an ultra‐rare autosomal dominant condition termed adult‐onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP). Cerebrovascular pathologies such as cerebral amyloid angiopathy (CAA) and perivascular p‐Tau 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 CSF‐1R 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‐1 (CSF‐1) and interleukin‐34 (IL‐34). Here, we show that depletion in CSF‐1R signalling induces BBB disruption and decreases the phagocytic capacity of peripheral macrophages but not microglia. CSF‐1R signalling appears to be critical for macrophage and microglial activation, and macrophage localisation to amyloid appears reduced following the induction of Csf‐1r heterozygosity in macrophages. Finally, we show that endothelial/microglial crosstalk and concomitant attenuation of CSF‐1R signalling causes re‐modelling of BBB‐associated tight junctions and suggest that regulating BBB integrity and systemic macrophage recruitment to the brain may be therapeutically relevant in ALSP and other Alzheimer’s‐like dementias.