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

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.

Choi C ，Park J ，Kim H ，Chang KT ，Park J ，Min KT ... -  《-》

Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease.

Da Mesquita S ，Louveau A ，Vaccari A ，Smirnov I ，Cornelison RC ，Kingsmore KM ，Contarino C ，Onengut-Gumuscu S ，Farber E ，Raper D ，Viar KE ，Powell RD ，Baker W ，Dabhi N ，Bai R ，Cao R ，Hu S ，Rich SS ，Munson JM ，Lopes MB ，Overall CC ，Acton ST ，Kipnis J ... -  《-》

Improvement of glymphatic-lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer's disease model.

Lee Y ，Choi Y ，Park EJ ，Kwon S ，Kim H ，Lee JY ，Lee DS ... -  《Scientific Reports》

Borneol-driven meningeal lymphatic drainage clears amyloid-β peptide to attenuate Alzheimer-like phenotype in mice.

Rationale: The accumulation and clearance of amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). The (re)discovery of meningeal lymphatic vessels in recent years has focused attention on the lymphatic clearance of Aβ and has become a promising therapeutic target for such diseases. However, there is a lack of small molecular compounds that could clearly regulate meningeal lymphatic drainage to remove Aβ from the brain. Methods: We investigated the effect of borneol on meningeal lymphatic clearance of macromolecules with different molecular weights (including Aβ) in the brain. To further investigate the mechanism of borneol regulating meningeal lymphatic drainage, immunofluorescence staining, western blotting, ELISA, RT-qPCR, and Nitric Oxide assay kits were used. The cognitive function of AD mice after borneol treatment was evaluated using two behavioral tests: open field (OF) and Morris water maze (MWM). Results: This study discovered that borneol could accelerate the lymphatic clearance of Aβ from the brain by enhancing meningeal lymphatic drainage. Preliminary mechanism analysis revealed that borneol could improve the permeability and inner diameter of lymphatic vessels, allowing macromolecules to drain into the cervical lymph nodes (CLNS) and then be transported to the lymphatic circulation. To speed up the clearance of macromolecules, borneol also stimulated lymphatic constriction by lowering the level of nitric oxide in the meninges. In addition, borneol stimulated lymphangiogenesis by increasing the levels of FOXC2, VEGFC, and LYVE-1 in the meninges, which promoted the clearance rates of macromolecules. Borneol improved meningeal lymphatic clearance not only for Aβ but also for other macromolecular polymers (molecular weight in the range of 2 KD - 45 KD. Borneol ameliorated cognitive deficits and alleviated brain Aβ burden in Aβ-injected mice. Conclusions: Our findings not only provide a strategy to regulate lymphatic clearance pathways of macromolecules in the brain, but also new targets and ideas for treating neurodegenerative diseases like AD. Furthermore, our findings indicate that borneol is a promising therapeutic drug for AD.

Wu Y ，Zhang T ，Li X ，Wei Y ，Li X ，Wang S ，Liu J ，Li D ，Wang S ，Ye T ... -  《Theranostics》

DSCR1 deficiency ameliorates the Aβ pathology of Alzheimer's disease by enhancing microglial activity.

Microglial phagocytosis and clearance are important for the removal of amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Chronic exposure of microglia to Aβ plaques leads to microglial metabolic dysfunction, and dysregulation of microglia can accelerate the deposition of Aβ plaques and cause learning and memory impairment. Thus, regulating microglial Aβ clearance is crucial for the development of therapeutics for AD-related dementia. Here, Down syndrome critical region 1 (DSCR1) deficiency ameliorated Aβ plaque deposition in the 5xFAD mouse model of AD by altering microglial activity; however, the Aβ synthesis pathway was not affected. DSCR1 deficiency improved spatial learning and memory impairment in 5xFAD mice. Furthermore, DSCR1-deficient microglia exhibited accelerated lysosomal degradation of Aβ after phagocytosis, and BV2 cells with stable knockdown of DSCR1 demonstrated enhanced lysosomal activity. RNA-sequencing analysis showed that the transcriptional signatures associated with responses to IFN-γ were significantly up-regulated in DSCR1-knockdown BV2 cells treated with Aβ. Our data strongly suggest that DSCR1 is a critical mediator of microglial degradation of amyloid plaques and a new potential microglial therapeutic target in AD.

Choi C ，Kim H ，Oh J ，Park C ，Kim M ，Kim CS ，Park J ... -  《Life Science Alliance》