Novel Perivascular Macrophage Mechanism to Promote Glymphatic Aβ Clearance After Stroke

BACKGROUND: Parenchymal border macrophages (PBMs) reside at the interface between the central nervous system and the periphery. They are known to mediate the accessibility of the substances to the brain. However, no one has examined their role in poststroke Aβ (amyloid-β) clearance. METHODS: Permanent focal cerebral ischemia was induced in 8- to 10-week-old C57/Bl6 male mice by distal middle cerebral artery occlusion. The clodronate liposomes were administered into the cerebral spinal fluid at 7 days before stroke to deplete the PBM population. Sensorimotor and cognitive functions, glymphatic system, and Aβ accumulation were assessed for up to 34 days after stroke. RESULTS: The Aβ accumulated along brain blood vessels after stroke in both the ipsilateral and contralateral hemispheres. When PBMs were depleted, glymphatic drainage of Aβ was markedly reduced, and this was accompanied by deterioration of cognitive function, highlighting a critical role for PBMs in poststroke Aβ disposal. A possible mechanism relates to MANF (mesencephalic astrocyte-derived neurotrophic factor). MANF derived from PBMs suppressed astrocytic stress and maintained glymphatic drainage when supplemented into the cerebral spinal fluid. In the chronic phase of stroke, MANF production in PBMs was downregulated, and consequently, glymphatic impairments were exacerbated, which led to ongoing Aβ accumulation and cognitive decline. CONCLUSIONS: In summary, supplementation of MANF not only mitigates the adverse impacts of PBM depletion but also exerts therapeutic effects that improve glymphatic system function. We thus propose that this represents a promising strategy to prevent poststroke cognitive impairment.