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

TL;DR

This study shows that meningeal lymphatic dysfunction in Alzheimer's mice begins at 6 months, offering a key window for early intervention.

Contribution

The study reveals a spontaneous decline in lymphatic function linked to early Aβ pathology in APP/PS1 mice.

Findings

APP/PS1 mice showed cognitive deficits and Aβ plaques at 6 months.

Lymphatic drainage and LYVE-1 expression were reduced in APP/PS1 mice at 6 months.

Early lymphatic dysfunction correlates with Aβ pathology progression.

Abstract

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.

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.

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.

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.

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