E2F4-Based Gene Therapy Mitigates the Phenotype of the Alzheimer's Disease Mouse Model 5xFAD
| Autor: | Alberto Garrido-García, Vanesa Cano-Daganzo, Noelia López-Sánchez, José María Frade, Morgan Ramón-Landreau |
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| Přispěvatelé: | Ministerio de Ciencia e Innovación (España), Tetraneuron, Ministerio de Industria y Competitividad (España) |
| Rok vydání: | 2021 |
| Předmět: |
Genetically modified mouse
Neuronal tetraploidy Genetic enhancement Morris water navigation task Mice Transgenic Microgliosis Mice Cell quiescence Neuroinflammation Alzheimer Disease E2F4 phosphorylation Medicine Animals Pharmacology (medical) Maze Learning E2F4 Tissue homeostasis Y-maze Pharmacology Amyloid beta-Peptides business.industry Genetic Therapy Aβ deposits Disease Models Animal Phenotype Cancer research Original Article Neurology (clinical) business |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Neurotherapeutics |
| ISSN: | 2018-0950 |
| Popis: | After decades of unfruitful work, no effective therapies are available for Alzheimer's disease (AD), likely due to its complex etiology that requires a multifactorial therapeutic approach. We have recently shown using transgenic mice that E2 factor 4 (E2F4), a transcription factor that regulates cell quiescence and tissue homeostasis, and controls gene networks affected in AD, represents a good candidate for a multifactorial targeting of AD. Here we show that the expression of a dominant negative form of human E2F4 (hE2F4DN), unable to become phosphorylated in a Thr-conserved motif known to modulate E2F4 activity, is an effective and safe AD multifactorial therapeutic agent. Neuronal expression of hE2F4DN in homozygous 5xFAD (h5xFAD) mice after systemic administration of an AAV.PHP.B-hSyn1.hE2F4DN vector reduced the production and accumulation of Aß in the hippocampus, attenuated reactive astrocytosis and microgliosis, abolished neuronal tetraploidization, and prevented cognitive impairment evaluated by Y-maze and Morris water maze, without triggering side effects. This treatment also reversed other alterations observed in h5xFAD mice such as paw-clasping behavior and body weight loss. Our results indicate that E2F4DN-based gene therapy is a promising therapeutic approach against AD. We thank M.J. Román for her technical help and C. Sánchez-Puelles for her critical reading of the manuscript. This work has been supported by Ministerio de Ciencia, Innovación y Universidades grant RTI2018-095030-B-I00 and a R&D contract between CSIC and Tetraneuron S.L. N.L.S. holds a Torres Quevedo grant from Ministerio de Industria. M.R.L. holds an Industrial Doctorate grant from Ministerio de Economía, Industria y Competitividad. |
| Databáze: | OpenAIRE |
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