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bioRxiv · 10.64898/2026.05.25.727443

An integrated human forebrain organoid reveals microglia-mediated CD8⁺ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology

MA, S.
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Abstract

Genetic evidence implicates immune dysfunction in Alzheimers disease (AD), yet the neuroimmune mechanisms operating in human tissue remain poorly defined. Here, we establish a modular human forebrain organoid platform that systematically integrates iPSC-derived microglia and CD8+ T cells to reconstitute multicellular Alzheimers disease pathology. This system enables functional interrogation of both innate and adaptive immune components in a human-relevant context. Using this platform, we demonstrate that microglia mediate amyloid-{beta} clearance and neuronal maturation but also drive inflammatory activation and recruit CD8+ T cells through CCL4/5 signaling via CCR1/5 and CXCR3, establishing a neuroinflammatory feedback loop. Pharmacological targeting of CCR5 or CXCR3 blocks T cell recruitment and modulates autophagy in a microglia-dependent manner. This modular organoid platform provides a versatile tool for dissecting neuron-immune interactions and enables cell-type-specific therapeutic screening in human neuroinflammatory disease models. Highlights1) A modular human forebrain organoid platform integrating innate (microglia) and adaptive (CD8+ T cells) immunity recapitulates key features of the human neuroimmune environment 2) Enables mechanistic dissection of multicellular interactions underlying Alzheimers disease pathology 3) Overcomes limitations of traditional animal models by resolving human-specific, cell-type-specific neuroimmune mechanisms 4) Establishes a new approach methodology for studying neuroimmune disorders and advancing drug discovery

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MA, S.. 2026-05-28. An integrated human forebrain organoid reveals microglia-mediated CD8⁺ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology. https://doi.org/10.64898/2026.05.25.727443

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