- LIPUS restores neurological function in TBI mice, improving motor coordination and memory while reducing tau pathology, amyloid beta and astrocyte reactivity.
- LIPUS activates Piezo1 on meningeal lymphatic endothelial cells, promoting proliferation, migration and restoration of lymphatic coverage and cerebrospinal fluid drainage.
- VEGFC is the critical downstream effector; its overexpression rescues meningeal lymphatic restoration and cerebrospinal fluid drainage.
Brain Stimul. 2026 Oct 28:103245. doi: 10.1016/j.brs.2026.103245. Online ahead of print.
ABSTRACT
BACKGROUND: Meningeal lymphatic vessels (mLVs) are specialized lymphatic structures that drain cerebrospinal fluid (CSF) and facilitate immune surveillance of the central nervous system. This drainage system is impaired after traumatic brain injury (TBI); mLVs undergo structural regression, and CSF outflow to peripheral lymphoid tissues is markedly slowed. The resulting accumulation of hyperphosphorylated tau, amyloid-β, and inflammatory mediators drives sustained neuroinflammation and cognitive decline. The neuroprotective effect of low-intensity pulsed ultrasound (LIPUS) in TBI mice has been previously demonstrated, however, its impact on brain lymphatic drainage is unclear.
METHODS: Here, we employed a controlled cortical impact (CCI) mouse model of TBI combined with serial LIPUS stimulation to investigate its therapeutic potential for mLV function.
RESULTS: LIPUS restored neurological function in TBI mice, improving motor coordination and spatial/recognition memory while attenuating tau pathology, Aβ burden, and astrocyte reactivity. Mechanistically, LIPUS activated Piezo1 on meningeal lymphatic endothelial cells (LECs), triggering a downstream signaling cascade that promoted LEC proliferation and migration in vitro and restored lymphatic coverage and drainage function in vivo. To identify the critical mediator of this process, we examined the pathway’s downstream components and found that vascular endothelial growth factor C (VEGFC) served as the critical downstream effector: VEGFC overexpression rescued meningeal lymphatic restoration and CSF drainage.
CONCLUSIONS: These results establish LIPUS as a non-invasive therapeutic strategy that functionally restores brain lymphatic drainage after TBI, representing a promising preclinical therapeutic strategy for proteinopathy-associated neurological diseases that warrants further optimization for clinical translation.
PMID:42951248 | DOI:10.1016/j.brs.2026.103245
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