ABSTRACT
Alzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aß) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aß in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aß passive immunotherapy by exacerbating the deposition of Aß, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aß by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Immunotherapy , Lymphatic Vessels/immunology , Meninges/immunology , Microglia/immunology , Aging/drug effects , Aging/immunology , Alzheimer Disease/genetics , Alzheimer Disease/immunology , Alzheimer Disease/pathology , Amyloid beta-Peptides/drug effects , Animals , Antibodies, Monoclonal, Humanized/immunology , Brain/blood supply , Brain/cytology , Brain/drug effects , Brain/immunology , Disease Models, Animal , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/immunology , Humans , Inflammation/drug therapy , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Male , Meninges/blood supply , Meninges/cytology , Mice , Microglia/cytology , Microglia/drug effects , Transcription, Genetic/drug effects , Vascular Endothelial Growth Factor C/metabolism , Vascular Endothelial Growth Factor C/pharmacologyABSTRACT
Lowering total tau levels is an attractive therapeutic strategy for Alzheimer's disease and other tauopathies. High-throughput screening in neurons derived from human induced pluripotent stem cells (iPSCs) is a powerful tool to identify tau-targeted therapeutics. However, such screens have been hampered by heterogeneous neuronal production, high cost and low yield, and multi-step differentiation procedures. We engineered an isogenic iPSC line that harbors an inducible neurogenin 2 transgene, a transcription factor that rapidly converts iPSCs to neurons, integrated at the AAVS1 locus. Using a simplified two-step protocol, we differentiated these iPSCs into cortical glutamatergic neurons with minimal well-to-well variability. We developed a robust high-content screening assay to identify tau-lowering compounds in LOPAC and identified adrenergic receptors agonists as a class of compounds that reduce endogenous human tau. These techniques enable the use of human neurons for high-throughput screening of drugs to treat neurodegenerative disease.