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-<i>BDNF</i> 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 (<i>Cecr2, Cdhr1, Dusp6, Pam, Rasd1, Dusp4, Htr5b, Tmem117</i>) and two downregulated genes (<i>Abhd14a</i>, <i>Pmel</i>). Notably, three genes - <i>Npy, Crh</i>, <i>Tac1</i>-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.