Regional mitochondrial DNA and cell-type changes in post-mortem brains of non-diabetic Alzheimer’s disease are not present in diabetic Alzheimer’s disease

Thubron, Elisabeth B, Rosa, Hannah S, Hodges, Angela, Sivaprasad, Sobha, Francis, Paul T, Pienaar, Ilse S and Malik, Afshan N (2019) Regional mitochondrial DNA and cell-type changes in post-mortem brains of non-diabetic Alzheimer’s disease are not present in diabetic Alzheimer’s disease. Scientific Reports, 9 (1). a11386. ISSN 2045-2322

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Background: Mitochondrial dysfunction is implicated in both diabetes and Alzheimer’s disease (AD), and diabetes also increases the risk of AD, however the combined impact of AD and diabetes on brain mitochondria is unknown. The purpose of this study was to test the hypothesis that the combination of both diabetes and AD exacerbates mitochondrial dysfunction.
Methods: Post-mortem human brains (n=74), were used to determine mitochondrial DNA (mtDNA) content of cerebellum, frontal cortex and parietal cortex by quantifying absolute mtDNA copy number/cell using real time qPCR. mtDNA content was compared between diabetic and non-diabetic cases representing non-cognitively impaired controls (NCI), mildly cognitively impaired (MCI) and AD. A subset of parietal cortex samples was used to quantify mRNAs corresponding to cell types and mitochondrial function. Immune-staining of parietal cortex sections followed by semi-automated stereological assessment was performed to assess cell types.
Results. Using mtDNA as an indicator of mitochondrial content, we observed significant regional variation, being highest in the parietal cortex, and lowest in the cerebellum. In the absence of diabetes, AD cases had decreased parietal cortex mtDNA, reduced MAP2 (neuronal) mRNA and increased GFAP (astrocyte) mRNA, relative to NCI. However, in the presence of both diabetes and AD, we did not observe these changes in the parietal cortex. Irrespective of cognitive status, all 3 brain regions in diabetic cases had significantly higher mtDNA than the non-diabetic cases.
Conclusion. Our data show that the parietal cortex has the highest mitochondrial content but is also the most vulnerable to changes in AD, as shown by reduced mtDNA and neurones in this region. In contrast, when patients have both diabetes and AD, the AD associated parietal cortex changes are no longer seen, suggesting that the pathology observed in diabetic AD may be different to that seen in non-diabetic AD. The lack of clear functional changes in mitochondrial parameters in diabetic AD suggest that there may be different mechanisms contributing to cognitive impairment in diabetes and their impact on the respective disease neuro-pathologies remain to be fully understood.

Item Type: Article
Keywords: Mitochondrial DNA; Diabetes; Alzheimer’s disease; Parietal cortex; Frontal cortex. Cerebellum, brain, dementia
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
Depositing User: Ilse Pienaar
Date Deposited: 15 Jul 2019 09:49
Last Modified: 12 Sep 2019 15:15

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