Aged T-cell-derived cytokines impact meningeal lymphatics and contribute to AD

PROJECT SUMMARY Many age-related neurodegenerative diseases—including Alzheimer's disease (AD)—are associated with misfolded protein deposition that promote inflammatory responses, neuronal dysfunction, and cognitive deficits. We have recently identified that aging and AD both display impaired meningeal lymphatic function, which ultimately results in impaired CSF drainage to deep cervical lymph nodes, as well as CSF perfusion into the brain parenchyma, collectively promoting waste build up and A-induced pathologies in AD mice. Our preliminary data demonstrate that aging is also associated with the accumulation of IFNγ-producing CD4 and CD8 T cells in the dural meninges, closely associated with the meningeal lymphatics. IFNγ signaling represents a transcriptional hallmark of aged meningeal lymphatics and augmentation of this axis in young mice attenuates their functional drainage of CSF. We therefore hypothesize that during aging and in AD, elevated expression of IFNγ from meningeal CD4 and CD8 T cells impairs meningeal lymphatic function function via direct signaling on their IFNγ receptors, leading to meningeal lymphatic deterioration. Such deterioration later results in impaired brain perfusion by cerebrospinal fluid (CSF), subsequently leading to the accumulation of debris and worsening progression of AD. We further hypothesize that using cytokine neutralizing antibodies, we can preserve meningeal lymphatics in aged mice and prevent or reduce the age-associated brain dysfunctions and augment existing immunotherapy strategies in AD patients. Addressing our hypotheses of this proposal will illuminate mechanistic pathways underlying age-related meningeal lymphatic dysfunction, and identify new promising avenues for therapeutic interventions intended to reduce AD-related pathology.