Public Attenuated CSF‐1R signalling drives cerebrovascular pathology

mat · Jan 5, 2021

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.
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This is a significant finding not only on the Alzheimer's front. Previously, the exact role of the immune system in early-onset Alzheimer's was unclear. Early-onset Alzheimer's is one of the diseases also showing overlaps with CFS/ME. This is one of the reasons why a differential classification of early-onset Alzheimer's and Diabetes 3 has become blurry as well. Diabetes 3 typically also involves issues with glycolysis. Whoever still keeps wondering how the immune system can directly cause neuroinflammation, here is the evidence.

doi: 10.15252/emmm.202012889

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Public Attenuated CSF‐1R signalling drives cerebrovascular pathology

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Public Attenuated CSF‐1R signalling drives cerebrovascular pathology

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