A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair in Alzheimer's Disease-Like Non-Human Primate Model.

Abstract

There is a pressing demand for neuroregenerative treatment for Alzheimer's disease (AD). Recently, a NeuroD1-mediated neuroregeneration strategy has been proposed, yet its efficacy remains untested in non-human primate (NHP) AD models closely reflecting human pathology. This study evaluates the therapeutic potential of NeuroD1 AAV-based gene therapy in an NHP AD model with hippocampal hTau overexpression, utilizing immunostaining, fluorescence/confocal imaging, MRI and FDG PET scans, Simoa CSF biomarker analysis, behavioral tests, and bulk RNA sequencing. NeuroD1 AAV-based gene therapy prevents neuronal damage and degeneration, inhibits hippocampal atrophy, and reduces neuroinflammation in NHP AD models. It also repairs vascular and BBB damage, restores CSF AD biomarker levels, improves hippocampal glucose metabolism, and enhances spatial working memory. Transcriptome analysis further reveals upregulated neuronal function and synaptic transmission, along with downregulated neuroinflammation and apoptosis. Collectively, our findings demonstrate that NeuroD1 AAV-based gene therapy repairs and restores brain structure and function in NHP AD models, highlighting its therapeutic potential.