Regional mitochondrial DNA and cell-type changes in post-mortem brains of non-diabetic Alzheimer\u2019s disease are not present in diabetic Alzheimer\u2019s disease

Elisabeth B. Thubron,Ilse S. Pienaar,Afshan N. Malik,Angela Hodges,Sobha Sivaprasad,Paul T. Francis,Hannah S. Rosa

doi:10.1038/s41598-019-47783-4

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.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, affecting an estimated 46 million people worldwide, with numbers predicted to rise to >130 million by 20501
Www.nature.com/scientificreports own extra-nuclear genome known as mitochondrial DNA, a small circular molecule of 16.5Kb which is present in multiple copies in cells. mtDNA content has been widely used as an indicator of mitochondrial content in cells, since the quantity of mtDNA can be measured from small amounts of biological samples using quantitative polymerase chain reaction and expressed as a ratio to the nuclear genome to allow the estimation of cellular mtDNA content[11]
The absolute amount of mtDNA, measured as mitochondrial genome copies per nuclear genome (MtN), was determined within the frontal cortex, parietal cortex and cerebellum using controls defined as non-cognitively impaired controls (NCI)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, affecting an estimated 46 million people worldwide, with numbers predicted to rise to >130 million by 20501. We determined mtDNA content of these regions in diabetic NCI cases and saw similar trends, with cerebellum having the lowest levels compared to frontal (3.3-fold greater) and parietal (4.7-fold greater) cortices (Fig. 1B).

Results

Conclusion