Transplantation of GABAergic Interneuron Progenitors Restores Cortical Circuit Function in an Alzheimer's Disease Mouse Model

Yokomizo, S.; Maci, M.; Stafford, A. M.; Miller, M. R.; Perle, S. J.; Takahashi, S.; Brown-Harding, H.; Liang, L.; Lovely, A.; Algamal, M.; Gillani, R. L.; Zwang, T. J.; Richardson, D.; Naegele, J. R.; Vogt, D.; Kastanenka, K. V.

doi:10.1101/2025.05.31.656412

bioRxiv · 10.1101/2025.05.31.656412

Transplantation of GABAergic Interneuron Progenitors Restores Cortical Circuit Function in an Alzheimer's Disease Mouse Model

Yokomizo, S.·Maci, M.·Stafford, A. M.·Miller, M. R.·Perle, S. J.·Takahashi, S.·Brown-Harding, H.·Liang, L.·Lovely, A.·Algamal, M.·Gillani, R. L.·Zwang, T. J.·Richardson, D.·Naegele, J. R.·Vogt, D.·Kastanenka, K. V.

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Abstract

In addition to dementia, Alzheimers patients suffer from sleep impairments and aberrations in sleep-dependent brain rhythms. Deficits in inhibitory GABAergic interneuron function disrupt one of those rhythms, slow oscillation in particular, and actively contribute to Alzheimers progression. We tested the degree to which transplantation of healthy donor interneuron progenitors would restore slow oscillation rhythm in young APP mice. We harvested medial ganglionic eminence (MGE) progenitors from mouse embryos and transplanted them into host APP mutant cortices. 3D light-sheet and structured illumination microscopy revealed that transplanted MGE progenitors survived and matured into healthy interneurons. In vivo multiphoton calcium imaging and voltage-sensitive dye imaging showed functional integration and slow oscillation rescue in absence or presence of optogenetic stimulation. Our work provides proof-of-concept evidence that stem cell therapy may serve as a viable strategy to rescue functional impairments in cortical circuits of APP mice and potentially those of Alzheimers patients.

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Yokomizo, S., Maci, M., Stafford, A. M., Miller, M. R., Perle, S. J., Takahashi, S., Brown-Harding, H., Liang, L., Lovely, A., Algamal, M., Gillani, R. L., Zwang, T. J., Richardson, D., Naegele, J. R., Vogt, D., Kastanenka, K. V.. 2025-06-01. Transplantation of GABAergic Interneuron Progenitors Restores Cortical Circuit Function in an Alzheimer's Disease Mouse Model. https://doi.org/10.1101/2025.05.31.656412

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