Attenuated CSF‐1R signalling drives cerebrovascular pathology

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.

Modeling CSF‐1 receptor deficiency diseases – how close are we?

“…Out of the 106 different CSF1R pathogenic mutations that were reported in 275 cases of CRL, 34 have been characterized in terms of expression and signaling [36,[44][45][46][47][48][49] (Table 3). Three mutations cause NMD and are therefore expected to produce haploinsufficiency [46,47,50].…”

“…Based on the finding that in the presence of CSF-1, the mutant receptors can bind CSF-1, but fail to support proliferation, the authors conclude that in heterozygous individuals, wild type/mutant CSF-1R heterodimers must be inactive. In doing so, they ignore the evidence provided by co-transfection experiments of wild type and mutant CSF1R constructs, in which the Accepted Article mutant chain did not significantly inhibit the phosphorylation of wild type CSF-1R in response to CSF-1 binding [49,51], indicating that a dominant-negative mechanism is unlikely. Indeed, unless overexpressed, the mutant receptor chains may not significantly impair signaling.…”

“…Several studies [25,49,71] suggest that recurring hypoxic-ischemic injuries might play a role. This hypothesis is supported by observations that myelin loss sometimes follows a perivascular rather than a diffuse, pattern [71], as well as reports of vascular changes, including small vessel adventitial fibrosis [25,71] and severe arteriosclerosis [49], in the subcortical white matter. In addition, Delaney et al Further exploration of the relationship between the loss of nonclassical monocytes and vascular and BBB fitness in CRL is needed.…”

“…[49] report widespread cerebral amyloid angiopathy and perivascular accumulation of phosphorylated tau in the meninges and parenchyma of three postmortem CRL cases and suggest that disruption of phagocyte-endothelial cell cross talk might result in altered blood brain barrier (BBB) function. It is not clear which phagocytic component, i.e.…”

Pathology of the neurovascular unit in leukodystrophies

“…A recent study showed amyloid-β depositions in blood vessels of ALSP patients, indicating cerebral amyloid angiopathy. This study proposed that the driving force behind ALSP pathology is systemic inflammation [ 122 ]. Neuroinflammation could also play a role in AxD that features perivascular and intraparenchymal T-lymphocytic infiltrates [ 123 – 126 ].…”