Natural progression of meningeal lymphatic dysfunction in APP/PS1 mice creates a critical window for Alzheimer's disease intervention.

BACKGROUND/AIM: Meningeal lymphatic vessels (mLVs) facilitate the clearance of toxic metabolites like amyloid-beta (Aβ) from the central nervous system. Dysfunction in MLVs is implicated in Alzheimer's disease (AD). However, current knowledge relies on exogenous intervention models that fail to capture spontaneous mLV decline during AD progression. In this study, we investigated the age-dependent correlation between mLV/deep cervical lymph node (dCLN) dysfunction and Aβ pathology in APP/PS1 mice under noninterventional conditions.

MATERIALS AND

METHODS

APP/PS1 and wild-type (WT) mice at 3, 6, and 9 months of age were evaluated. Cognitive function was tested using the Morris water maze. mLV/dCLN drainage was assessed by intracisternal Texas Red dextran 3 injection. Lymphatic structure/function and Aβ pathology were analyzed via immunohistochemistry, immunofluorescence, and tracer penetration.

RESULTS

APP/PS1 mice developed significant cognitive deficits at 6 and 9 months. Aβ plaques emerged at 6 months and progressed by 9 months in APP/PS1 mice, but were absent in controls. At 6 months, APP/PS1 mice had reduced tracer drainage in mLVs/dCLNs, decreased LYVE-1 expression, and impaired tracer penetration in the hippocampus/cortex compared to WT mice.

CONCLUSION

Lymphatic functional decline starts at 6-months old, providing a critical timeframe for early AD intervention. Our findings underscore the value of the APP/PS1 model for studying lymphatic clearance mechanisms in AD.