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

Viewed as an imbalance between production and clearance of toxic A{beta} peptides, Alzheimers disease is a candidate for therapies to augment brain waste removal. Prior work has shown that A{beta} accumulates in meninges with aging as a byproduct of normal brain activity, in parallel with build-up of A{beta} oligomers in neurons, blood vessels, and interstitial fluid. Using the TgF344-AD rat model of Alzheimers disease, we now report that dural lymphatic vessels specifically accumulate neurotoxic pyroglutamate amyloid beta (pE3-A{beta}) with aging. Notably, accelerated amyloidosis is observed in meninges after ligation of cervical lymphatics, together with significantly increased pE3-A{beta} and A{beta}42 deposition in upstream brain regions implicated in Alzheimers disease. Blockade of lymphatic clearance is not sufficiently compensated by other efflux pathways, suggesting a necessary role of A{beta} clearance at the level of lymphatics. We further report that dural lymphatic cells actively clear A{beta} via energy-dependent mechanisms, and lymphatic A{beta} transport is significantly impaired both in normal aging and in Alzheimers 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-A{beta} with aging, similar to the rat model. We conclude that intracranial meningeal and extracranial cervical lymphatic vessels are targets for Alzheimers disease therapies focused on improving amyloid clearance. One Sentence SummaryLymphatic vessels remove A{beta} from the brain via energy-dependent active transport mechanisms, and blockage of extracranial lymphatic drainage is sufficient to cause significant acceleration of intracranial Alzheimers A{beta} pathology in both meninges and brain.