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Energy-dependent transport at dural lymphatic vessels is necessary for Aβ brain clearance in Alzheimer's disease

By Liudmila Romanova, Heidi Phillips, Gregory S. Calip, Kyle Hauser, Daniel A Peterson, Orly Lazarov, Daniel Predescu, Sanda Predescu, Julie Schneider, Jeff Kordower, Eric Hansen, Cornelius H. Lam, Christopher G. Janson

Posted 05 Feb 2019
bioRxiv DOI: 10.1101/427617

Viewed as an imbalance between production and clearance of toxic Aβ peptides, Alzheimer's disease is a candidate for therapies to augment brain waste removal. Prior work has shown that Aβ accumulates in meninges with aging as a byproduct of normal brain activity, in parallel with build-up of Aβ oligomers in neurons, blood vessels, and interstitial fluid. Using the TgF344-AD rat model of Alzheimer's disease, we now report that dural lymphatic vessels specifically accumulate neurotoxic pyroglutamate amyloid beta (pE3-Aβ) with aging. Notably, accelerated amyloidosis is observed in meninges after ligation of cervical lymphatics, together with significantly increased pE3-Aβ and Aβ42 deposition in upstream brain regions implicated in Alzheimer's disease. Blockade of lymphatic clearance is not sufficiently compensated by other efflux pathways, suggesting a necessary role of Aβ clearance at the level of lymphatics. We further report that dural lymphatic cells actively clear Aβ via energy-dependent mechanisms, and lymphatic Aβ transport is significantly impaired both in normal aging and in Alzheimer's disease. Dural lymphatic cells isolated from the TgF344-AD rat show ultrastructural abnormalities in mitochondria and abnormal cytoplasmic inclusions, with a distinct transcriptional profile implicating failure of energy-dependent transport. Finally, using human meninges treated with FocusDeep tissue clearing, we demonstrate using whole mount panoramic imaging that dural lymphatic vessels comprise a structurally diverse intracranial vascular network that accumulates pE3-Aβ with aging, similar to the rat model. We conclude that intracranial meningeal and extracranial cervical lymphatic vessels are targets for Alzheimer's disease therapies focused on improving amyloid clearance.

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