Harnessing Meningeal Lymphatics and Immunity to Alleviate APOE4-Induced Brain Dysfunction

2021

Alzheimer’s disease (AD) is an aging-related disorder characterized by the accumulation of toxic proteins (including aggregates of amyloid proteins) in the brain and ultimately neuronal death, leading to severe cognitive deficits. Aging and the altered expression of certain genes, including APOE4, represent major risk factors for AD. The central nervous system is wrapped by a protective tissue called the meninges that contain a functional lymphatic vascular network. The lymphatic vessels of the meninges are constantly draining brain fluids, excrete toxic molecular waste products and influence immune responses in the brain. We previously have shown that an age-dependent reduction in brain drainage by the meningeal lymphatic vessels significantly impacts different aspects of AD pathogenesis, including brain amyloid deposition. However, little is known about the impact of the AD gene risk factor APOE4 on the meningeal immune response and lymphatic vasculature. Using preclinical mouse models, we will explore whether and how the therapeutic modulation of the immune response in the meninges and of brain drainage by the meningeal lymphatic vessels impacts brain function in the context of APOE4 expression and increased risk for AD.


Funding to Date

$172,500

Focus

Studies of Alternative Neurodegenerative Pathways, Translational

Researchers

Sandro Da Mesquita, Ph.D.