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Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration

Heng Du1, Lan Guo1, Xiaoping Wu2

  • 1Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.

Biochimica Et Biophysica Acta
|March 20, 2013
PubMed

Insights

Blocking Cyclophilin D (CypD) prevents amyloid beta-induced mitochondrial dysfunction and synaptic loss in Alzheimer's disease models. This highlights CypD's role in oxidative stress and PKA/CREB pathway disruption, crucial for synaptic health.

Area of Science:

  • Neuroscience
  • Mitochondrial Biology
  • Neurodegenerative Diseases

Background:

  • Alzheimer's disease (AD) features early neuronal mitochondrial pathology and synaptic dysfunction.
  • Cyclophilin D (CypD) is implicated in amyloid beta (Aβ)-induced mitochondrial dysfunction via the mitochondrial permeability transition pore (mPTP).
  • CypD inhibition shows potential in preventing Aβ-induced cognitive deficits.

Purpose of the Study:

  • To investigate the role of CypD in Aβ-mediated oxidative stress, synaptic dysfunction, and the PKA/CREB signaling pathway.
  • To determine if blocking CypD can protect neurons from Aβ-induced synaptic damage.
  • To elucidate the mechanism linking mitochondrial oxidative stress to synaptic injury via the PKA/CREB pathway.

Main Methods:

  • Utilized antioxidants (probucol, SOD/catalase) to assess the impact of reactive oxygen species (ROS) on neuronal signaling and synapses.
  • Examined Aβ-induced changes in CypD-deficient neurons, focusing on ROS levels, PKA/cAMP regulatory-element-binding (CREB) pathway activity, and synaptic integrity.
  • Compared CypD-deficient mice expressing amyloid precursor protein (mAPP) with control mAPP mice to evaluate synaptic density, dendritic spine maturation, and synaptic activity.

Main Results:

  • Antioxidant treatment blocked Aβ-mediated inactivation of the PKA/CREB pathway and synapse loss, indicating oxidative stress's detrimental effect.
  • CypD-deficient neurons exhibited reduced Aβ-induced ROS and were resistant to Aβ-disrupted PKA/CREB signaling, showing increased PKA activity and CREB phosphorylation.
  • Lack of CypD protected neurons from Aβ-induced synaptic loss and dysfunction; CypD-deficient mAPP mice displayed improved synaptic density and function compared to controls.

Conclusions:

  • CypD-dependent mitochondrial oxidative stress is a key mechanism driving synaptic injury in Alzheimer's disease.
  • The PKA/CREB signaling pathway is a critical mediator linking oxidative stress to synaptic dysfunction.
  • Targeting CypD offers a potential therapeutic strategy to mitigate mitochondrial dysfunction and synaptic damage in AD.
Keywords:
Alzheimer's diseaseAmyloid betaMitochondrial permeability transitionOxidative stressPKA/CREB signalingSynaptic alteration

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