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Novel Perivascular Macrophage Mechanism to Promote Glymphatic Aβ Clearance After Stroke
Chunyi Li1,2, Tiemei Li1, Mengyan Hu1
1Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (C.L., T.L., M.H., X.K., X.S., S.W., D.L., S.S., H.H., X.D., Y.L., Z.L., W.C.).
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.
Insights
Parenchymal border macrophages (PBMs) are crucial for clearing amyloid-beta (Aβ) after stroke. Supplementing with MANF improves glymphatic function and cognitive outcomes, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Immunology
- Cerebrovascular Research
Background:
- Parenchymal border macrophages (PBMs) are strategically located at the brain-periphery interface and influence substance entry into the central nervous system.
- The specific role of PBMs in clearing amyloid-beta (Aβ) following a stroke has not been previously investigated.
Purpose of the Study:
- To investigate the role of PBMs in post-stroke Aβ clearance and its impact on cognitive function.
- To explore the potential therapeutic effects of mesencephalic astrocyte-derived neurotrophic factor (MANF) in mitigating stroke-induced impairments.
Main Methods:
- Focal cerebral ischemia was induced in mice via middle cerebral artery occlusion.
- PBMs were depleted using clodronate liposomes administered intrathecally prior to stroke induction.
- Assessment included sensorimotor and cognitive functions, glymphatic system activity, and Aβ accumulation up to 34 days post-stroke.
Main Results:
- Stroke led to Aβ accumulation in both hemispheres, with reduced glymphatic drainage and cognitive decline upon PBM depletion.
- Mesencephalic astrocyte-derived neurotrophic factor (MANF) derived from PBMs was found to suppress astrocytic stress and maintain glymphatic drainage.
- Downregulation of MANF in PBMs during the chronic stroke phase exacerbated glymphatic impairment, Aβ accumulation, and cognitive decline.
Conclusions:
- PBMs play a critical role in post-stroke Aβ clearance and maintaining glymphatic function.
- MANF supplementation demonstrated therapeutic potential by improving glymphatic system function and mitigating adverse effects of PBM depletion.
- MANF represents a promising therapeutic strategy for preventing post-stroke cognitive impairment.
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