Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD
D A Cottrell1, E L Blakely, M A Johnson
1Department of Neurology, The Medical School, University of Newcastle upon Tyne, UK. d.a.cottrell@ncl.ac.uk
Objective:
To determine whether hippocampal neurons and choroidal epithelial cells demonstrate a mitochondrial enzyme deficiency in AD more frequently than in normal aging.
Background:
High levels of mutant mitochondrial DNA (mtDNA) cause a deficiency in cytochrome c oxidase (COX) (complex IV activity) because three of its 13 subunits are encoded for by mtDNA. In contrast, succinate dehydrogenase (SDH) (complex II activity) remains intact because all of its subunits are nuclear encoded. The histologic hallmark of cells containing high levels of mtDNA mutation in both primary mtDNA disorders and normal aging muscle is the presence of COX-deficient SDH-positive cells.
Methods:
The authors applied a sequential histochemical method for COX and SDH to hippocampal sections in 17 AD and 17 age-matched control brains. This confers the advantages of both looking at individual cells in situ and measuring the actual mitochondrial complex activity rather than simply the complex quantity.
Results:
COX-deficient SDH-positive hippocampal neurons and choroidal epithelial cells are more prevalent in patients with AD than in controls. In addition the COX-deficient SDH-positive choroidal cells are associated with an enlargement in size.
Conclusion:
This increase in number of COX-deficient SDH-positive hippocampal pyramidal neurons and choroid epithelial cells provides strong evidence that a substantial mitochondrial enzyme activity defect occurs in individual cells more frequently in AD than in normal aging and that mitochondria may play a significant role in the pathogenesis of AD.
Insights
Mitochondrial enzyme deficiency in brain cells is more common in Alzheimer's disease (AD) than in normal aging. This suggests mitochondria play a key role in AD development.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mutant mitochondrial DNA (mtDNA) can cause deficiencies in cytochrome c oxidase (COX), a key mitochondrial enzyme.
- Succinate dehydrogenase (SDH) activity remains intact as its subunits are nuclear-encoded.
- COX-deficient, SDH-positive cells indicate high mtDNA mutation levels, seen in aging and disease.
Purpose of the Study:
- To investigate if hippocampal neurons and choroidal epithelial cells show mitochondrial enzyme deficiency more often in Alzheimer's disease (AD) compared to normal aging.
Main Methods:
- A histochemical method was used to assess COX and SDH activity in hippocampal sections from AD and control brains.
- This method allowed for in situ analysis of individual cells and direct measurement of mitochondrial enzyme activity.
Main Results:
- COX-deficient, SDH-positive hippocampal neurons and choroidal epithelial cells were found more frequently in AD patients than in controls.
- Enlarged choroidal cells with COX deficiency and SDH positivity were observed in AD.
Conclusions:
- The increased prevalence of COX-deficient, SDH-positive cells in AD brains provides evidence for mitochondrial enzyme defects in individual cells.
- These findings strongly suggest that mitochondria play a significant role in the pathogenesis of Alzheimer's disease.
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