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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by a gradual decline in cognitive function and is the most common cause of dementia in the elderly
Following ligation to colony stimulating factor-1 receptor (CSF-1R), the ligand is taken into the cell, reducing the extracellular concentration and preventing long-term local CSF-1R activity
Within the brain of an individual with ALSP microglia will constitutively express 50% less functional CSF-1R. This likely results in a CNS saturated with IL-34 and colony stimulating factor-1 (CSF-1) and increased levels of CSF-1 have previously been observed in the CSF-1R-knockout mouse and in some mouse models of AD (Dai et al, 2002; Laske et al, 2010)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by a gradual decline in cognitive function and is the most common cause of dementia in the elderly. Up to 80% of AD patients display cerebrovascular pathologies such as cerebral amyloid angiopathy (CAA) as well as in over 30% of cases of non-Alzheimer’s dementia (Matthews et al, 2009). The underlying mechanism that leads to Aβ accumulation in this perivascular pattern is still not fully understood. It is accepted, that CAA can contribute to dementia onset and cognitive decline through increasing susceptibility for microbleeds, cerebral ischaemia and chronic activation of pro-inflammatory mechanisms in the surrounding parenchyma (Kinnecom et al, 2007; Vukic et al, 2009)
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