Attenuated CSF-1R signalling drives cerebrovascular pathology

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Cerebrovascular pathologies and blood-brain barrier (BBB) disruption are common in Alzheimer's disease (AD), but mechanisms remain unclear.
• Adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare autosomal dominant condition with cerebrovascular pathologies like cerebral amyloid angiopathy (CAA).

Purpose of the Study:

• To investigate the role of colony stimulating factor-1 receptor (CSF-1R) mutations in ALSP.
• To elucidate the impact of CSF-1R signaling on BBB integrity and macrophage function.
• To explore therapeutic targets for ALSP and AD-like dementias.

Main Methods:

• Identified novel CSF-1R mutations in two families with ALSP.
• Assessed the effect of CSF-1R signaling depletion on BBB integrity and macrophage phagocytosis in vitro and in vivo.
• Analyzed endothelial/microglial crosstalk and tight junction remodeling.

Main Results:

• CSF-1R variants in ALSP patients result in loss of kinase activity.
• Reduced CSF-1R signaling disrupts the BBB and impairs peripheral macrophage phagocytosis.
• CSF-1R signaling is crucial for macrophage and microglial activation and amyloid localization.

Conclusions:

• CSF-1R signaling is essential for maintaining BBB integrity and regulating macrophage function.
• Endothelial/microglial crosstalk and impaired CSF-1R signaling contribute to BBB remodeling in ALSP.
• Targeting BBB integrity and macrophage recruitment offers potential therapeutic strategies for ALSP and Alzheimer's-like dementias.