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beta-Amyloid peptide induces ultrastructural changes in synaptosomes and potentiates mitochondrial dysfunction in the
Xavier Mungarro-Menchaca1, Patricia Ferrera, Julio Morán
1Departamento de Biología Celular y Fisiologia, Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de México, D.F.
Abstract:
In Alzheimer's disease (AD), loss of synapses exceeds neuronal loss and some evidence suggests a role of beta-amyloid protein (Abeta) in synaptic degeneration through a mechanism which may involve intraneuronal Ca2+ dyshomeostasis. Emerging evidence points to the participation of the internal Ca2+ stores in the pathophysiology of neurodegeneration in AD. To test the involvement of intrasynaptic Ca2+ mobilization in A toxicity, we explored the role of ryanodine receptor activation in rat cortical synaptosomes taken as a model system for the central presynapses. Evaluation of synaptosomal mitochondrial redox capacity was assessed by the MTT reduction technique, and ultrastructural changes of synaptosomes after exposure to Abeta and ryanodine were evaluated by electron microscopy. Our results show that Abeta potentiates mitochondrial dysfunction in the presence of ryanodine and induces morphological changes consisting of mitochondrial swelling and intense small synaptic vesicles depletion. These changes were accompanied by a reduction in the content of synaptophysin and actin proteins. The reduction of actin immunoreactivity was reversed in the presence of a wide range caspase inhibitors, suggesting the activation of synaptic apoptotic mechanisms.
Insights
Beta-amyloid protein (Abeta) exacerbates mitochondrial dysfunction in Alzheimer's disease (AD) synaptosomes. Ryanodine receptor activation and Abeta trigger synaptic vesicle depletion and apoptosis, highlighting a role for intracellular calcium stores in AD synaptic degeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Synaptic loss in Alzheimer's disease (AD) is a key pathological feature.
- Beta-amyloid protein (Abeta) is implicated in synaptic degeneration.
- Intracellular calcium (Ca2+) dyshomeostasis may contribute to AD pathophysiology.
Purpose of the Study:
- To investigate the role of intrasynaptic Ca2+ mobilization in Abeta toxicity.
- To explore the involvement of ryanodine receptor activation in synaptic degeneration in AD models.
Main Methods:
- Utilized rat cortical synaptosomes as a model for central presynapses.
- Assessed mitochondrial redox capacity using the MTT reduction technique.
- Evaluated ultrastructural changes via electron microscopy after exposure to Abeta and ryanodine.
Main Results:
- Abeta potentiated mitochondrial dysfunction in the presence of ryanodine.
- Observed synaptosome morphological changes: mitochondrial swelling and synaptic vesicle depletion.
- Reduced levels of synaptophysin and actin proteins were noted.
- Caspase inhibitors reversed actin reduction, suggesting synaptic apoptosis.
Conclusions:
- Ryanodine receptor activation contributes to Abeta-induced synaptic damage.
- Intrasynaptic Ca2+ release and mitochondrial dysfunction are critical in AD synaptic pathology.
- Synaptic apoptosis, mediated by caspase activation, is involved in Abeta toxicity.