The protein BDNF is known to encourage neuroplasticity in the brain and otherwise assist in protecting the health and function of neurons. Numerous studies have demonstrated upregulation of BDNF to improve cognitive function in the context of aging and neurodegenerative conditions. Much of this work focuses on very indirect paths to the upregulation of BDNF, such as manipulation of the gut microbiome, but here researchers take the direct approach of a viral gene therapy introduced into brain tissue via stereotactic injection. They show that this can improve cognitive function in mouse models of Alzheimer's disease
Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of in vivo BDNF delivery requires further optimization, and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated. Here, we demonstrated that a newly engineered adeno-associated virus (AAV) serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system (CNS).
We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models: amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3xTg. Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice, and alleviated their cognitive impairment, with no discernible effect on amyloid-β deposition or tau phosphorylation. Furthermore, transcriptomic analysis in 3xTg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions, such as Neuropeptide Y (Npy), Corticotropin-releasing hormone (Crh), Tachykinin precursor 1 (Tac1), and the down-regulation of Bone morphogenetic proteins (Bmps).
Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD, which will be useful for future translational research on AD treatment using an AAV delivery system.
Link: https://doi.org/10.1016/j.gendis.2025.101649
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