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RNA silencing of genes involved in Alzheimer's disease enhances mitochondrial function and synaptic activity

Maria Manczak1, P Hemachandra Reddy

  • 1Neurogenetics Laboratory, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.

Biochimica Et Biophysica Acta
|September 26, 2013
PubMed

Insights

Reducing amyloid precursor protein (APP), Tau, and voltage-dependent anion channel 1 (VDAC1) gene expression may protect against Alzheimer's disease (AD) by improving synaptic activity and mitochondrial function. This suggests potential therapeutic value for AD patients.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • Alzheimer's disease (AD) is linked to increased mRNA levels of amyloid precursor protein (APP), Tau, and voltage-dependent anion channel 1 (VDAC1) genes, which are toxic to neurons.
  • The precise toxic mechanisms of these genes in AD pathogenesis remain incompletely understood.

Purpose of the Study:

  • To investigate the effects of RNA silencing of APP, Tau, and VDAC1 genes on Alzheimer's disease (AD) pathogenesis.
  • To assess the impact of reducing APP, Tau, and VDAC1 expression on synaptic function and mitochondrial health in a cellular model of AD.

Main Methods:

  • Utilized human neuroblastoma (SHSY5Y) cells for RNA silencing experiments targeting APP, Tau, and VDAC1 genes.
  • Employed real-time RT-PCR to quantify mRNA levels of 34 AD-related genes.
  • Conducted biochemical assays to evaluate mitochondrial function, including H2O2 production, lipid peroxidation, and enzyme activities (cytochrome c oxidase, ATP, GTPase).

Main Results:

  • RNA silencing of APP, Tau, and VDAC1 led to increased mRNA expression of synaptic function and mitochondrial fission genes, alongside decreased mitochondrial fusion gene expression.
  • Biochemical analyses revealed reduced H2O2 production, lipid peroxidation, and fission-linked GTPase activity in silenced cells.
  • Silenced cells exhibited enhanced cytochrome c oxidase activity and ATP production, indicating improved mitochondrial function.

Conclusions:

  • Reduction of APP, Tau, and VDAC1 mRNA expression may enhance synaptic activity and improve mitochondrial maintenance and function.
  • Targeting these genes could offer protection against the toxicities associated with Alzheimer's disease (AD)-related genes.
  • Downregulation of APP, Tau, and VDAC1 presents a potential therapeutic strategy for AD patients.
Keywords:
Amyloid precursor proteinHuman neuroblastoma cellImmunoblotting analysisRNA silencingTauVoltage-dependent anion channel

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