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Novel MicroRNA-455-3p and its protective effects against abnormal APP processing and amyloid beta toxicity in

Subodh Kumar1, Arubala P Reddy2, Xiangling Yin3

  • 1Internal Medicine Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, United States.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|June 11, 2019
PubMed

Insights

MicroRNA-455-3p protects against Alzheimer's disease by regulating amyloid precursor protein processing and improving mitochondrial and synaptic health. This microRNA offers a potential therapeutic target for Alzheimer's disease.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Alzheimer's disease (AD) is characterized by abnormal amyloid precursor protein (APP) processing, amyloid beta (Aβ) formation, mitochondrial dysfunction, and synaptic damage.
  • MicroRNAs (miRNAs) play crucial roles in regulating gene expression and are implicated in various neurological disorders, including AD.

Purpose of the Study:

  • To investigate the protective role of miR-455-3p against aberrant APP processing, Aβ production, mitochondrial deficits, and synaptic impairment in Alzheimer's disease progression.
  • To identify and validate APP as a direct target of miR-455-3p.

Main Methods:

  • In-silico analysis to predict miR-455-3p targets.
  • Luciferase reporter assays to confirm miR-455-3p binding to the APP 3'UTR.
  • Biochemical and molecular assays (immunoblot, ELISA, RT-qPCR) to quantify APP, Aβ, mitochondrial, and synaptic markers.
  • Immunofluorescence and transmission electron microscopy (TEM) to assess mitochondrial morphology and synaptic structures.

Main Results:

  • miR-455-3p directly targets the APP gene.
  • Overexpression of miR-455-3p in mutant APP cells reduced levels of mutant APP, Aβ(1-40), Aβ(1-42), and C99.
  • miR-455-3p restored mitochondrial biogenesis and dynamics by modulating key regulatory proteins (PGC1α, NRFs, TFAM, DRP1, FIS1, OPA1, Mfn1/2).
  • miR-455-3p increased the expression of synaptic proteins (synaptophysin, PSD95) and improved mitochondrial morphology.

Conclusions:

  • miR-455-3p plays a significant protective role in mitigating AD pathology.
  • This microRNA effectively regulates APP processing and counteracts mutant APP-induced mitochondrial and synaptic abnormalities.
  • miR-455-3p represents a promising therapeutic candidate for Alzheimer's disease.
Keywords:
Alzheimer's diseaseAmyloid betaAmyloid precursor proteinMitochondrial biogenesisSynaptic proteinsmicroRNA-455-3p

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