SHED-Derived Exosomes Attenuate Alzheimer's Disease Pathology in iPSC-Derived Cerebral Organoid Model

Abstract Introduction: Developing disease-modifying therapies for Alzheimer’s disease (AD) that go beyond single-target monoclonal antibodies is a pressing translational priority. Stem cells from human exfoliated deciduous teeth (SHED) and their exosomal cargo represent a promising biological therapy. To bridge the gap between basic exosome research and clinical application, we evaluated SHED-derived exosomes in human-relevant 2D and 3D patient-derived models. Methods: Induced pluripotent stem cell (iPSC)-derived 2D cortical neurons and 3D cerebral organoid models were generated from patients representing both familial AD (FAD; PSEN1) and sporadic AD (SAD). Models were treated with SHED-derived exosomes. Pathological markers including p181-tau, Aβ42, and Aβ40 were quantified, functional excitotoxicity was assessed via N-methyl-D-aspartate (NMDA)-induced calcium dynamics, and mitochondrial reactive oxygen species (ROS) were measured. High-throughput microRNA (miRNA) profiling was performed to identify functional exosomal cargo. Results: SHED exosome treatment demonstrated genotype-specific efficacy, selectively reducing p181-tau levels and restoring the p181-tau/Aβ42 ratio in FAD lines while elevating the protective Aβ42/Aβ40 ratio across both FAD and SAD backgrounds. Functionally, treatment prevented NMDA-induced calcium overload, accelerated intracellular calcium clearance, and suppressed stress-induced mitochondrial ROS. High-throughput profiling identified enriched therapeutic miRNAs (hsa-miR-23a-3p, hsa-miR-16-5p, and hsa-miR-191-5p) targeting key networks in tau hyperphosphorylation and amyloid processing. Discussion: SHED-derived exosomes attenuate key AD pathologies and functional excitotoxicity in human 2D and 3D organoid models. These findings provide translational validation for exosome-based therapeutics, helping close the knowledge gap in multi-target biological treatments for dementia.