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

Area of Science:

• Neuroscience
• Immunology
• Vascular Biology

Background:

• Meningeal lymphatic vessels (mLVs) clear toxic metabolites like amyloid-beta (Aβ) from the central nervous system.
• mLV dysfunction is linked to Alzheimer's disease (AD), but spontaneous decline during AD progression is poorly understood.
• This study investigates age-dependent mLV/deep cervical lymph node (dCLN) dysfunction and Aβ pathology in APP/PS1 mice without external interventions.

Purpose of the Study:

• To investigate the age-dependent correlation between mLV/dCLN dysfunction and Aβ pathology in APP/PS1 mice.
• To establish a noninterventional model for studying lymphatic clearance in AD.
• To identify potential early intervention timeframes for AD based on lymphatic function.

Main Methods:

• Evaluated APP/PS1 and wild-type (WT) mice at 3, 6, and 9 months.
• Assessed cognitive function using the Morris water maze.
• Measured mLV/dCLN drainage via intracisternal Texas Red dextran 3 injection and analyzed lymphatic structure/function and Aβ pathology using immunohistochemistry, immunofluorescence, and tracer penetration.

Main Results:

• APP/PS1 mice exhibited cognitive deficits and Aβ plaque accumulation starting at 6 months.
• Reduced tracer drainage in mLVs/dCLNs, decreased LYVE-1 expression, and impaired hippocampal/cortical tracer penetration were observed in 6-month-old APP/PS1 mice compared to WT.
• These findings indicate lymphatic functional decline begins by 6 months in this AD model.

Conclusions:

• Lymphatic functional decline commences by 6 months of age, suggesting a critical window for early AD intervention.
• The APP/PS1 mouse model is valuable for studying age-dependent lymphatic clearance mechanisms in Alzheimer's disease.
• Understanding spontaneous mLV decline is crucial for developing effective AD therapies.