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bioRxiv · 10.1101/2024.12.17.628978

Neuronal expression of E2F4DN restores adult neurogenesis in homozygous 5xFAD mice via TrkB signaling

Lozano-Urena, A.·Llabres-Mas, A. M.·Ramon-Landreau, M.·Fraj-Cebrian, A.·Sanchez-Puelles, C.·Garrido-Garcia, A.·Cano-Daganzo, V.·Valdes-Lora, L.·Frade, J. M.
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Abstract

The etiology of Alzheimers disease (AD) has been associated with impaired neurogenesis in the adult subventricular zone (SVZ), but the molecular mechanism leading to this impairment remains poorly understood. Neuronal dysfunction in the AD-affected brain might lead to reduced production of neuron-derived paracrine factors acting through receptors necessary for adult SVZ neurogenesis (ASN). To test this hypothesis, we focused on the TrkB receptor, which can transduce signals from the neurotrophins BDNF and NT4/5, since TrkB is known to regulate the ASN process and its function becomes altered in AD. Here we show that ASN is impaired in the SVZ of homozygous 5xFAD (h5xFAD) mice. This impairment is prevented by administering an AAV.PHP.eB vector that expresses in neurons the transcription factor E2F4 carrying the Thr249Ala/Th251Ala mutation (E2F4DN), a gene therapeutic approach previously demonstrated to exert multifactorial effects in this mouse model of AD. The use of culture media conditioned by primary cortical neurons expressing E2F4DN was able to recover the proliferative and differentiative capacity of neural stem cells (NSCs) isolated from h5xFAD mice. This effect was blocked by inhibiting the TrkB receptor. Accordingly, TrkB activation mimicked the effect of the E2F4DN-conditioned medium on the proliferative and differentiative capacity of h5xFAD NSCs, a finding consistent with the upregulation of NT4/5 expression in the E2F4DN-transduced neurons. We conclude that the activation of TrkB by neurotrophins released by E2F4DN-expressing neurons can recover the ASN phenotype in 5xFAD mice. Therefore, the multifactorial therapeutic capacity of E2F4DN includes the recovery of impaired ASN through the upregulation of TrkB signaling in NSCs.

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Lozano-Urena, A., Llabres-Mas, A. M., Ramon-Landreau, M., Fraj-Cebrian, A., Sanchez-Puelles, C., Garrido-Garcia, A., Cano-Daganzo, V., Valdes-Lora, L., Frade, J. M.. 2024-12-17. Neuronal expression of E2F4DN restores adult neurogenesis in homozygous 5xFAD mice via TrkB signaling. https://doi.org/10.1101/2024.12.17.628978

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