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Abstract
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.
Keywords
HEREDITARY DIFFUSE LEUKOENCEPHALOPATHY, ADULT-ONSET LEUKOENCEPHALOPATHY, NEURONAL LOSS, MICROGLIA, RECEPTOR, IL-34, MACROPHAGES, INHIBITION, SPHEROIDS, MONOCYTES, adult&#8208, onset leucoencephalopathy with axonal spheroids and, pigmented glia (ALSP), blood, brain barrier, CSF&#8208, 1, CSF&#8208, 1R, IL&#8208, 34

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Citation

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MLA
Delaney, Conor, et al. “Attenuated CSF-1R Signalling Drives Cerebrovascular Pathology.” EMBO MOLECULAR MEDICINE, vol. 13, no. 2, 2021, doi:10.15252/emmm.202012889.
APA
Delaney, C., Farrell, M., Doherty, C. P., Brennan, K., O’Keeffe, E., Greene, C., … Campbell, M. (2021). Attenuated CSF-1R signalling drives cerebrovascular pathology. EMBO MOLECULAR MEDICINE, 13(2). https://doi.org/10.15252/emmm.202012889
Chicago author-date
Delaney, Conor, Michael Farrell, Colin P. Doherty, Kiva Brennan, Eoin O’Keeffe, Chris Greene, Kieva Byrne, et al. 2021. “Attenuated CSF-1R Signalling Drives Cerebrovascular Pathology.” EMBO MOLECULAR MEDICINE 13 (2). https://doi.org/10.15252/emmm.202012889.
Chicago author-date (all authors)
Delaney, Conor, Michael Farrell, Colin P. Doherty, Kiva Brennan, Eoin O’Keeffe, Chris Greene, Kieva Byrne, Eoin Kelly, Niamh Birmingham, Paula Hickey, Simon Cronin, Savvas Savvides, Sarah L. Doyle, and Matthew Campbell. 2021. “Attenuated CSF-1R Signalling Drives Cerebrovascular Pathology.” EMBO MOLECULAR MEDICINE 13 (2). doi:10.15252/emmm.202012889.
Vancouver
1.
Delaney C, Farrell M, Doherty CP, Brennan K, O’Keeffe E, Greene C, et al. Attenuated CSF-1R signalling drives cerebrovascular pathology. EMBO MOLECULAR MEDICINE. 2021;13(2).
IEEE
[1]
C. Delaney et al., “Attenuated CSF-1R signalling drives cerebrovascular pathology,” EMBO MOLECULAR MEDICINE, vol. 13, no. 2, 2021.
@article{8697689,
  abstract     = {{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.}},
  articleno    = {{e12889}},
  author       = {{Delaney, Conor and Farrell, Michael and Doherty, Colin P. and Brennan, Kiva and O'Keeffe, Eoin and Greene, Chris and Byrne, Kieva and Kelly, Eoin and Birmingham, Niamh and Hickey, Paula and Cronin, Simon and Savvides, Savvas and Doyle, Sarah L. and Campbell, Matthew}},
  issn         = {{1757-4676}},
  journal      = {{EMBO MOLECULAR MEDICINE}},
  keywords     = {{HEREDITARY DIFFUSE LEUKOENCEPHALOPATHY,ADULT-ONSET LEUKOENCEPHALOPATHY,NEURONAL LOSS,MICROGLIA,RECEPTOR,IL-34,MACROPHAGES,INHIBITION,SPHEROIDS,MONOCYTES,adult&#8208,onset leucoencephalopathy with axonal spheroids and,pigmented glia (ALSP),blood,brain barrier,CSF&#8208,1,CSF&#8208,1R,IL&#8208,34}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{17}},
  title        = {{Attenuated CSF-1R signalling drives cerebrovascular pathology}},
  url          = {{http://dx.doi.org/10.15252/emmm.202012889}},
  volume       = {{13}},
  year         = {{2021}},
}

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