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

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.