Recent Advances in Microglia Modelling to Address Translational Outcomes in Neurodegenerative Diseases

Neurodegenerative diseases are deteriorating conditions of the nervous system that are rapidly increasing in the ageing population. Increasing evidence suggests that neuroinflammation, largely mediated by microglia, the resident immune cells of the brain, contributes to the onset and progression of neurodegenerative diseases. Hence, microglia are considered a major therapeutic target that could potentially yield effective disease-modifying treatments for neurodegenerative diseases. Despite the interest in studying microglia as drug targets, the availability of cost-effective, flexible, and patient-specific microglia cellular models is limited. Importantly, the current model systems do not accurately recapitulate important pathological features or disease processes, leading to the failure of many therapeutic drugs. Here, we review the key roles of microglia in neurodegenerative diseases and provide an update on the current microglial plaforms utilised in neurodegenerative diseases, with a focus on human microglia-like cells derived from peripheral blood mononuclear cells as well as human-induced pluripotent stem cells. The described microglial platforms can serve as tools for investigating disease biomarkers and improving the clinical translatability of the drug development process in neurodegenerative diseases

Altered Brain Endothelial Cell Phenotype from a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery

The blood-brain barrier (BBB) presents a barrier for circulating factors, but simultaneously challenges drug delivery. How the BBB is altered in Alzheimer disease (AD) is not fully understood. To facilitate this analysis, we derived brain endothelial cells (iBECs) from human induced pluripotent stem cells (hiPSCs) of several patients carrying the familial AD PSEN1 mutation. We demonstrate that, compared with isogenic PSEN1 corrected and control iBECs, AD-iBECs exhibit altered tight and adherens junction protein expression as well as efflux properties. Furthermore, by applying focused ultrasound (FUS) that transiently opens the BBB and achieves multiple therapeutic effects in AD mouse models, we found an altered permeability to 3-5 kDa dextran as a model cargo and the amyloid-beta (A beta) peptide in AD-iBECs compared with control iBECs. This presents human-derived in vitro models of the BBB as a valuable tool to understand its role and properties in a disease context, with possible implications for drug delivery.Peer reviewe

Additional file 1 of Advanced patient-specific microglia cell models for pre-clinical studies in Alzheimer’s disease

Additional file 1. Supplementary figures