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<p>In Alzheimer’s disease (AD), brain levels of Brain-derived neurotrophic factor (BDNF) are reduced. BDNF, a neurotrophin involved in neuronal development and plasticity, has a protective role against the cytotoxic effects of Aβ, a pathological hallmark of AD. Since therapeutic approaches to increase BDNF levels by supplementing BDNF directly in the nervous system have been ineffective, we explored an alternative strategy: to increase intracellular BDNF levels by using synthetic SINEUP long non-coding RNAs which upregulate protein synthesis without altering mRNA levels. We designed one SINEUP common to all BDNF transcripts (SINEUP-PAN) and one SINEUP complementary to the BDNF 5’exon-I transcript (SINEUP-Ex1), which is downregulated in AD and not expressed in non-neuronal tissues. SINEUPs activity and specificity have been first proven on endogenous targets in different mammalian cell lines – human neuroblastoma cells, rat neurons and mouse astrocytes. During in vitro development of naïve primary rat hippocampal neurons, SINEUP-Ex1, but not SINEUP-PAN, induced more complex dendritic arborisations at 12 days in vitro (DIV12). In DIV6 neurons, 24&#xa0;h incubation with aggregated Aβ<sub>25−35</sub> peptide caused neuronal atrophy and both SINEUP-PAN and SINEUP-Ex1 promoted the full rescue of soma size, apical dendrite diameter, and number of dendritic endpoints, but not of the total dendritic length. The protection from the Aβ-challenge achieved with the two SINEUPs appear to involve distinct mechanisms, as only SINEUP-PAN was able to increase Map2, a marker of dendritic microtubules which show aberrations in AD. These results support SINEUP as a potential new tool for a gene-therapy in AD and other neurodegenerative diseases.</p>

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Long non-coding SINEUP RNA enhancing BDNF translation prevents dendritic atrophy following an Aβ-peptide challenge

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月14日

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  • Marta Atzori,
  • Elsa Fabbretti,
  • Viviana Ciraci,
  • Silvia Zucchelli,
  • Carlotta Bon,
  • Sanja Mikašinović,
  • Gabriele Baj,
  • Stefano Gustincich,
  • Enrico Tongiorgi

摘要

In Alzheimer’s disease (AD), brain levels of Brain-derived neurotrophic factor (BDNF) are reduced. BDNF, a neurotrophin involved in neuronal development and plasticity, has a protective role against the cytotoxic effects of Aβ, a pathological hallmark of AD. Since therapeutic approaches to increase BDNF levels by supplementing BDNF directly in the nervous system have been ineffective, we explored an alternative strategy: to increase intracellular BDNF levels by using synthetic SINEUP long non-coding RNAs which upregulate protein synthesis without altering mRNA levels. We designed one SINEUP common to all BDNF transcripts (SINEUP-PAN) and one SINEUP complementary to the BDNF 5’exon-I transcript (SINEUP-Ex1), which is downregulated in AD and not expressed in non-neuronal tissues. SINEUPs activity and specificity have been first proven on endogenous targets in different mammalian cell lines – human neuroblastoma cells, rat neurons and mouse astrocytes. During in vitro development of naïve primary rat hippocampal neurons, SINEUP-Ex1, but not SINEUP-PAN, induced more complex dendritic arborisations at 12 days in vitro (DIV12). In DIV6 neurons, 24 h incubation with aggregated Aβ25−35 peptide caused neuronal atrophy and both SINEUP-PAN and SINEUP-Ex1 promoted the full rescue of soma size, apical dendrite diameter, and number of dendritic endpoints, but not of the total dendritic length. The protection from the Aβ-challenge achieved with the two SINEUPs appear to involve distinct mechanisms, as only SINEUP-PAN was able to increase Map2, a marker of dendritic microtubules which show aberrations in AD. These results support SINEUP as a potential new tool for a gene-therapy in AD and other neurodegenerative diseases.