The goal of this project is to explore the functional alterations in the brain-draining meningeal lymphatic vasculature induced by aging, sex and APOE genotype. Our experimental results show that there are sex-dependent morphological changes in meningeal lymphatic vasculature induced by APOE4 expression. Taking into consideration our data that points to macrophages as one of the main sources of APOE in the brain meninges, we will evaluate the effect of manipulating macrophage responses to decrease the levels of APOE4 in the meningeal dura of aged mice and normalize meningeal lymphatic function. We will further test whether vascular growth factor signaling can be therapeutically employed to restore meningeal lymphatic function in aged mice expressing human APOE4.
This proposal will provide mechanistic insights about the crosstalk between aging, APOE4 and meningeal lymphatic vessel dysfunction—three factors that were shown to affect Alzheimer’s disease-related amyloid pathology and the appearance of cognitive deficits. The data generated in this project will provide the foundations for future basic and clinical studies exploring therapeutic strategies to improve brain lymphatic drainage in Alzheimer’s disease.
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.