DSCR1 upregulation enhances dural meningeal lymphatic drainage to attenuate amyloid pathology of Alzheimer's disease

Abstract Highly developed meningeal lymphatics remove waste products from the brain. Disruption of meningeal lymphatic vessels in a mouse model of amyloid pathology (5XFAD) accelerates the accumulation of amyloid plaques in the meninges and brain, and causes learning and memory deficits, suggesting that clearance of toxic wastes by lymphatic vessels plays a key role in neurodegenerative diseases. Here, we discovered that DSCR1 (Down syndrome critical region 1, known also as RCAN1, regulator of calcineurin 1) facilitates the drainage of waste products by increasing the coverage of dorsal meningeal lymphatic vessels. Furthermore, upregulation of DSCR1 in 5XFAD mice diminishes Aβ pathology in the brain and improves memory defects. Surgical ligation of cervical lymphatic vessels afferent to dcLN blocks the beneficial effects of DSCR1 on Aβ accumulation and cognitive function. Interestingly, intracerebroventricular delivery of AAV1‐ DSCR1 to 5XFAD mice is sufficient to rebuild the meningeal lymphatic system and re‐establish cognitive performance. Collectively, our data indicate that DSCR1 facilitates the growth of dorsal meningeal lymphatics to improve drainage efficiency and protect against Alzheimer's disease (AD) pathologies, further highlighting that improving meningeal lymphatic function is a feasible treatment strategy for AD. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.