Alzheimers Disease Patient Brain Extracts Induce Multiple Pathologies In Novel Vascularized Neuroimmune Organoids For Disease Modeling And Drug Discovery Yanru Ji Xiaoling Chen Zhen Wang Connor Joseph Meek Jenna Lillie Mclean Yang Yang Chongli Yuan Jeanchristophe Rochet Fei Liu Ranjie Xu by Yanru Ji & Xiaoling Chen & Zhen Wang & Connor Joseph Meek & Jenna Lillie Mclean & Yang Yang & Chongli Yuan & Jean-christophe Rochet & Fei Liu & Ranjie Xu 101038/S4138002503041W instant download after payment.

Alzheimer’s Disease (AD) is the most common cause of dementia, afflicting 55 million individuals worldwide, with limited treatmentavailable. Current AD models mainly focus on familial AD (fAD), which is due to genetic mutations. However, models for studyingsporadic AD (sAD), which represents over 95% of AD cases without specific genetic mutations, are severely limited. Moreover, thefundamental species differences between humans and animals might significantly contribute to clinical failures for AD therapeuticsthat have shown success in animal models, highlighting the urgency to develop more translational human models for studying AD,1234567890();,:particularly sAD. In this study, we developed a complex human pluripotent stem cell (hPSC)-based vascularized neuroimmuneorganoid model, which contains multiple cell types affected in human AD brains, including human neurons, microglia, astrocytes, andblood vessels. Importantly, we demonstrated that brain extracts from individuals with sAD can effectively induce multiple ADpathologies in organoids four weeks post-exposure, including amyloid beta (Aβ) plaque-like aggregates, tau tangle-like aggregates,neuroinflammation, elevated microglial synaptic pruning, synapse/neuronal loss, and impaired neural network activity. Proteomicsanalysis also revealed disrupted AD-related pathways in our vascularized AD neuroimmune organoids. Furthermore, after treatmentwith Lecanemab, an FDA-approved antibody drug targeting Aβ, AD brain extracts exposed organoids showed a significant reductionof amyloid burden, along with an elevated vascular inflammation response. Thus, the vascularized neuroimmune organoid modelprovides a unique opportunity to study AD, particularly sAD, under a pathophysiological relevant three-dimensional (3D) human cellenvironment. It also holds great promise to facilitate AD drug development, particularly for immunotherapies.Molecular Psychiatry;