BDNF gene therapy rescues neuronal function via unique and common transcriptional responses in Aβ and tau-driven Alzheimer's disease mouse models

Brain-derived neurotrophic factor (BDNF) protects neurons from degeneration, making it a promising therapeutic target for Alzheimer's disease (AD). However, the genetic regulation resulting from BDNF overexpression in the brain remains to be further illustrated. Using APP/PS1 and rTg4510 mouse models, we analyzed hippocampal transcriptomes after intrahippocampal AAVT42-BDNF injection. In APP/PS1 mice with Aβ accumulation, BDNF upregulated genes involved in neuronal signaling and downregulated neurodegenerative pathways. In rTg4510 mice with p-tau pathology, upregulated genes were associated with cell differentiation and neuronal development, while downregulated genes were related to metabolism and biosynthesis. A comparison of differentially expressed genes (DEGs) between the two strains identified eight commonly upregulated genes (Cecr2, Cdhr1, Dusp6, Pam, Rasd1, Dusp4, Htr5b, Tmem117) and two downregulated genes (Abhd14a, Pmel). Notably, three genes - Npy, Crh, Tac1-were upregulated in both models, suggesting shared neuroprotective mechanisms. These findings reveal distinct and common genetic responses to BDNF in Aβ and p-tau pathogenesis, supporting its potential as a therapeutic strategy for AD.