Meningeal lymphatics and B cells in Alzheimer’s disease: A role in anti-amyloid beta immunotherapy?

Alzheimer’s disease (AD) is a devastating aging-associated neurodegenerative disorder and the leading cause of dementia. One of the pathological hallmarks of this disease is the accumulation and aggregation of neurotoxic amyloid beta (Aβ) peptides, thought to contribute to cognitive decline. While currently there is no effective treatment for AD, passive and active immunization against amyloid beta peptides are promising therapeutic strategies. In the central nervous system (CNS), with the exception of microglia in the brain parenchyma, the majority of the immune cells populate the interfaces between the brain and periphery, namely the meninges and choroid plexus. Yet, little is known about the meningeal adaptive immune response to Aβ, the role of B cells and endogenous antibody production in AD. Importantly, recent work from the Kipnis lab shows that changes in the drainage capacity of the meningeal lymphatic vessels affects brain function in mouse models of AD. Whether impaired meningeal lymphatic drainage impacts on B cell response, antibody production or antibody diffusion through the brain and Aβ removal in AD warrants further investigation. Here we will explore the specific changes in the meningeal immune response that are triggered by increased brain amyloid burden in mouse models of AD, with a special emphasis on meningeal B cell response. We also focus on the role of meningeal immunity upon immunotherapeutic interventions in a scenario of intact or dysfunctional meningeal lymphatic drainage. Understanding these interactions within the meningeal compartment might provide insight into current and future immunotherapies developed to treat AD.