Multiplex meningeal lymphatic activation for Alzheimer’s disease

PROJECT SUMMARY/ABSTRACT
There is an unmet medical need to develop new therapeutic strategies for Alzheimer’s disease (AD). Brain
lymphatic vasculature is (re)discovered at the interface between skull and brain (meninges) and is a pathogenic
factor for AD. We recently found that meningeal lymphatic dysfunction drives neurocognitive defects in
craniosynostosis disorder and established three independent approaches to activate brain lymphatics (Cell,
2021, PMID: 33417861; Cell Stem Cell, 2023, PMID: 37863055). The goal of this proposal is to determine
whether craniosynostosis is a risk factor for AD and how our multiplex brain lymphatic activation approaches can
be re-deployed to mitigate AD. These three approaches include the transcranial delivery of VEGF-C recombinant
protein, intra-cisterna magna (i.c.m.) injection of AAV1-VEGF-C gene, and MSC implantation. They are derived
from our investigation of skull-brain communication via skull mesenchymal stem cells (MSCs) and meningeal
lymphatic endothelial cells (LECs) crosstalk in health and craniosynostosis. Craniosynostosis is a major
craniofacial skull disorder characterized by the premature skull bone fusion due to suture MSC loss coupled with
neurocognitive defects. Our meningeal lymphatic investigation in Twist1+/- craniosynostosis mice provides a
foundational framework for structural and functional studies of brain lymphatics. Further mechanistic studies
revealed that skull MSCs directly promote LEC growth via VEGF-C signaling. Preliminary data identified an
abnormal buildup of amyloid β in Twist1+/- mouse brain, which is further exacerbated in the background of 5xFAD
mouse model of AD. We are in a unique position to re-deploy these discoveries and multiplex tools to promote
brain lymphatics as a therapeutic treatment for AD. We hypothesize that craniosynostosis is a risk factor for AD
due to its impaired meningeal lymphatics, and lymphatic activation by multiplex approaches can promote brain
fluid homeostasis and waste clearance, mitigating AD-like pathologies and behaviors. The successful outcome
of this study will determine the efficacy of individual brain lymphatic activation approaches in promoting brain
fluid homeostasis and waste clearance to mitigate AD pathogenesis.

Grant Number: 5R21AG089268-02
NIH Institute/Center: NIH
Principal Investigator: Jianfu Chen