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bioRxiv · 10.1101/2025.05.15.654007

Amyloid-beta deposition and reduced drainage at the cribriform plate lymphatics in APP/PS1 mouse model of Alzheimer's Disease

Vrba, S. M.·Laaker, C. J.·Limkar, A. R.·Hsu, M.·Ricke, W. A.·Ulland, T. K.·Pehar, M.·Sandor, M.·Fabry, Z.
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Abstract

Alzheimers disease (AD) is the most common cause of dementia, leading to substantial personal, economic, and medical costs to patients and society; it is characterized by the build-up of toxic amyloid-beta (A{beta}) and hyperphosphorylated tau. It is crucial to the health of the brain that these proteins are processed or drained effectively, but mounting research has shown that in AD pathology there is dysfunction in the ability of the brain to effectively clear pathological A{beta} and tau. In this report, we detail the involvement of one important brain drainage pathway and potential site of A{beta} clearance, the cribriform plate lymphatics, in 24-month old APP/PS1 mice. We show that cerebrospinal fluid (CSF) efflux is decreased across the cribriform plate area utilizing multiple methods. Moreover, we demonstrate that A{beta} aggregates at the cribriform plate - coating surface of olfactory bulbs (OB), olfactory nerve (ON) bundles, and cribriform plate lymphatic endothelial cells (cpLECs). At 24-months, APP/PS1 mice have increased CD45+ cell infiltration and decreased LYVE-1+ vessel area at the cribriform plate, suggesting local inflammation and lymphatic atrophy. Additionally, cpLECs have higher expression of caspase-3 suggesting the decreased LYVE-1 area is due to cellular toxicity resulting in apoptosis. This study demonstrates that the cribriform plate is an important area for further research elucidating its contribution to AD disease pathogenesis.

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Vrba, S. M., Laaker, C. J., Limkar, A. R., Hsu, M., Ricke, W. A., Ulland, T. K., Pehar, M., Sandor, M., Fabry, Z.. 2025-05-19. Amyloid-beta deposition and reduced drainage at the cribriform plate lymphatics in APP/PS1 mouse model of Alzheimer's Disease. https://doi.org/10.1101/2025.05.15.654007

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