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An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
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Impaired Fast Network Oscillations and Mitochondrial Dysfunction in a Mouse Model of Alpha-synucleinopathy (A30P).
Emma Robson1, Clare Tweedy1, Nelson Manzanza1
1Institute of Neuroscience, Newcastle University, Medical School, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK.
Neuroscience
|March 11, 2018
Summary
Abnormal alpha-synuclein (α-syn) expression impairs mitochondrial function and gamma oscillations in aging mice, potentially contributing to cognitive decline in Lewy body dementias.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Neurodegenerative Diseases
Background:
- Intracellular accumulation of alpha-synuclein (α-syn) is a hallmark of Lewy body dementias (LBDs), such as Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB).
- LBDs are characterized by significant cognitive impairments and alterations in brain network activity.
Purpose of the Study:
- To investigate how abnormal α-syn expression affects cortical network oscillations, specifically gamma frequency activity in the hippocampus, which is crucial for cognitive function.
- To explore the underlying mechanisms, including mitochondrial dysfunction, contributing to these network changes.
Main Methods:
- Utilized a mouse model overexpressing human mutant α-syn (A30P).
- Recorded hippocampal network oscillations in brain slices from young (2-6 months) and aged (9-16 months) A30P and control mice.
- Assessed mitochondrial function using mitochondrial blockers (potassium cyanide, rotenone) and measured cytochrome c oxidase (COX) activity and expression.
Main Results:
- Aged A30P mice exhibited an age-dependent reduction in gamma (20-80 Hz) oscillation power, not observed in young A30P or control mice.
- Mitochondrial blockers caused a greater reduction in network oscillations in aged A30P mice compared to controls.
- Histochemical and immunohistochemical analyses revealed age-dependent decreases in COX activity and COX IV expression in aged A30P mice, indicating mitochondrial dysfunction.
Conclusions:
- Overexpression of α-syn leads to age-dependent mitochondrial dysfunction.
- Impaired mitochondrial function is associated with reduced gamma frequency network activity in the hippocampus.
- These findings offer mechanistic insights into how α-syn pathology may drive cognitive decline in LBDs.
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