P007 - MIR-277 TARGETS HID TO AMELIORATE AΒ42-MEDIATED NEURODEGENERATION IN DROSOPHILA EYE MODEL OF ALZHEIMER’S DISEASE
Abstract
Aims
Alzheimer’s disease (AD), an age-related progressive neurodegenerative disorder, exhibits reduced cognitive functions with no cure to date. One of the reasons for AD is the extracellular accumulation of Amyloid-beta 42 (Aβ42) plaques. Accumulation of Aβ42 plaque(s) triggers aberrant signaling resulting in neuronal cell death by an unknown mechanism(s). microRNAs regulate the gene expression of the components which are involved in signaling pathways. We wanted to look for microRNAs involved in neurodegeneration
Methods
We misexpressed human Aβ42 in the developing retina of Drosophila, which exhibits AD-like neuropathology. We screened for microRNA which post-transcriptionally regulates expression of genes by degrading mRNA of the target genes. In a forward genetic screen with candidate miRNAs, we identified mir-277 as a genetic modifier of Aβ42-mediated neurodegeneration.
Results
Gain-of-function of mir-277 rescues Aβ42 mediated neurodegeneration whereas loss-of-function of mir-277 enhances Aβ42 mediated neurodegeneration. Moreover, misexpression of higher levels of mir-277 in the GMR>Aβ42 background restores the retinal axonal targeting indicating functional rescue. Furthermore, we have identified head involution defective (Hid) as one of the targets of mir-277 by Fly TargetScan and validated by luciferase assay and qPCR. The hid transcript levels are decreased by one third when mir-277 is misexpressed in the GMR>Aβ42 background in comparison to the GMR>Aβ42 fly model.
Conclusions
Hence, here we provide a mechanism of how mir-277 modulates Aβ42 mediated neurodegeneration by regulating hid transcript levels and demonstrate its neuroprotective role in Aβ42-mediated neuropathology.
