Abstract
BackgroundMitochondrial dysfunction may play a central role in the pathologic process of Alzheimer’s disease (AD), but there is still a scarcity of data that directly links the pathology of AD with the alteration of mitochondrial DNA. This study aimed to provide a comprehensive assessment of mtDNA rearrangement events in AD brain tissue.Patients and MethodsPostmortem frozen human brain cerebral cortex samples were obtained from the Banner Sun Health Research Institute Brain and Body Donation Program, Sun City, AZ. Mitochondria were isolated and direct sequence by using MiSeq®, and analyzed by relative software.ResultsThree types of mitochondrial DNA (mtDNA) rearrangements have been seen in post mortem human brain tissue from patients with AD and age matched control. These observed rearrangements include a deletion, F-type rearrangement, and R-type rearrangement. We detected a high level of mtDNA rearrangement in brain tissue from cognitively normal subjects, as well as the patients with Alzheimer's disease (AD). The rate of rearrangements was calculated by dividing the number of positive rearrangements by the coverage depth. The rearrangement rate was significantly higher in AD brain tissue than in control brain tissue (17.9%versus 6.7%; p = 0.0052). Of specific types of rearrangement, deletions were markedly increased in AD (9.2% versus 2.3%; p = 0.0005).ConclusionsOur data showed that failure of mitochondrial DNA in AD brain might be important etiology of AD pathology.
Highlights
Research suggests that mitochondrial changes are a driving force, rather than a consequence, of the aging process and Alzheimer’s disease (AD) pathogenesis [1]
This study aimed to provide a comprehensive assessment of mitochondrial DNA (mtDNA) rearrangement events in AD brain tissue
Three types of mitochondrial DNA rearrangements have been seen in post mortem human brain tissue from patients with AD and age matched control
Summary
Research suggests that mitochondrial changes are a driving force, rather than a consequence, of the aging process and AD pathogenesis [1]. Continuous replication of mitochondrial DNA is required for assignment to new mitochondria, resulting in a significant error rate and accumulation of mutated in mtDNA genome over time and space. Beyond point mutations, different types of mtDNA rearrangements should be extensively distributed in aging cells. As these rearrangements are often not detected by routine methods such as polymerase chain reaction, we applied approach by directly sequencing mtDNA from isolated mitochondria of fresh frozen brain samples and count. Our data show that different types of mitochondrial rearrangements are very common in both aging brain and Alzheimer’s disease (AD) brain. This study aimed to provide a comprehensive assessment of mtDNA rearrangement events in AD brain tissue.
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