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, 9 (1), 11386

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

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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

Elisabeth B Thubron et al. Sci Rep.

Abstract

Diabetes increases the risk of Alzheimer's disease (AD), and mitochondrial dysfunction is implicated in both diseases, however the impact of both diabetes and AD on brain mitochondria is not known. We measured mitochondrial DNA (mtDNA), an indicator of mitochondrial function, in frontal, parietal, and cerebellar regions of post-mortem human brains (n = 74) from non-cognitively impaired controls (NCI), mild-cognitively impaired (MCI) and AD cases. In a subset of parietal cortices, we measured mRNAs corresponding to cell types and mitochondrial function and semi-automated stereological assessment was performed on immune-staining of parietal cortex sections. mtDNA showed significant regional variation, highest in parietal cortex, and lowest in cerebellum. Irrespective of cognitive status, all brain regions had significantly higher mtDNA in diabetic cases. In the absence of diabetes, AD parietal cortices had decreased mtDNA, reduced MAP2 (neuronal) and increased GFAP (astrocyte) mRNA, relative to NCI. However, in the presence of diabetes, we did not observe these AD-related changes, 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 different cellular mechanisms contributing to cognitive impairment in diabetes which remain to be fully understood.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Regional difference in mtDNA content in non-cognitively impaired human brain. Cellular mtDNA content (MtN) of three brain regions was determined in cases defined as no cognitive impairment (NCI) without diabetes (a) and with diabetes (b). mtDNA content per case is shown by open circles (non-diabetic) or black dots (diabetic), with mean ± standard deviation(SD) and range of MtN for frontal cortex, parietal cortex and cerebellum shown in the tables below the graphs. Error bars for mean ± SD for each region. P-values determined by one-way ANOVA on log-transformed data. *p < 0.001, **p < 0.0001
Figure 2
Figure 2
Reduced mtDNA content in the parietal cortex of non-diabetic Alzheimer’s disease cases. Cellular mtDNA content (MtN) in the frontal cortex, parietal cortex and cerebellum from non-diabetic (a) and diabetic (b) cases defined as having no cognitive impairment (NCI, circles), mild cognitive impairment (MCI, squares), and Alzheimer’s disease (AD, triangles) with the grouped mean ± standard deviation(SD) and range of MtN values in the panels below. A significant change in MtN with AD is seen only in the parietal cortex of non-diabetic cases. Data points show mean cellular mtDNA content per case with error bars for mean ± SD per group. One-way ANOVA performed on log-transformed data *p = 0.0184.
Figure 3
Figure 3
mtDNA content is not reduced in parietal cortex of diabetic Alzheimer’s disease patients. Cellular mtDNA content (MtN) was measured in frontal cortex, parietal cortex and cerebellum from non-diabetic cases with no cognitive impairment (NCI, open circles), non-diabetic Alzheimer’s disease patients (AD, open triangles), and diabetic AD patients (black triangles). Points show mean MtN per case with error bars for mean ± SD per group. A significant reduction in MtN is seen in parietal cortex of non-diabetic AD patients, but not in diabetic AD patients. One-way ANOVA performed on log-transformed data *p < 0.05, relative to NCI non-diabetic group.
Figure 4
Figure 4
Changes to TFAM levels, transcription ratio and cell population in non-diabetic Alzheimer’s disease. Relative mRNA levels of TFAM, MT-ND1, MT-ND6, MAP2, GFAP and AIF1 (normalised to RLP13) were measured in parietal cortex of cases defined as non-diabetic with no cognitive impairment (NCI, n = 8, white bars), non-diabetic with Alzheimer’s disease (AD, n = 8, grey bars) and diabetic AD (n = 4, black bars). and standardised against non-diabetic NCI mean as a control. Cellular TFAM mRNA levels are reduced in non-diabetic AD (a). Transcription of mtDNA-encoded mRNAs MT-ND1 and MT-ND6 is increased in non-diabetic AD (b). Cell-specific markers for neurons (MAP2), astrocytes (GFAP) and microglia (AIF1) indicate cell-population changes in non-diabetic AD (c). Bars show the mean ± SEM per group. *p < 0.05 unpaired t-test on log-transformed data.
Figure 5
Figure 5
Immunostaining of parietal cortex sections. Immunohistochemical staining was performed on 7 µm thick frozen sections of parietal cortex of non-cognitively impaired controls (NCI, n = 8 sections, 4 cases) and Alzheimer’s Disease cases (AD, n = 7 sections, 4 cases). Immunoreactivity for transcription factor A mitochondrial (TFAM) (a,b) was quantified using reciprocal integrated density (ID) (c). Neuron, astrocyte and microglia cell numbers were determined by semi-stereological analysis of HuC/D (d,e), glial fibrillar acidic protein (GFAP) (g,h) and ionised calcium-binding adapter molecule 1 (IBA1) (j,k) immunoreactivity, with average number of cells per mm2 area quantified using random sampling analyses (f,i,l). Bars show the mean ± SD.

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