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2012 Grants - Sondheimer
Alzheimer's Disease and the Destabilization of the Mitochondrial Genome
Neal Sondheimer, M.D., Ph.D.
The Children's Hospital of Philadelphia
2012 New Investigator Research Grant
Mitochondria are cellular components that normally provide energy and nutrients to the cell. During Alzheimer's disease, however, mitochondrial function becomes altered and may lead to brain cell damage and cognitive decline. Changes in mitochondrial DNA (or genetic material) are likely responsible for such dysfunction. Yet scientists do not know exactly how mitochondrial irregularities are associated with Alzheimer's onset and progression.
In an effort to study these irregularities, Neal Sondheimer, M.D., and colleagues will use a novel method of identifying mitochondrial DNA in brain tissue. Previous research has focused on single mutations of mitochondrial DNA. But the technique used by Dr. Sondheimer's team (known as single-molecule real time sequencing) will enable it to locate and analyze numerous mutations across the human genome. In the first part of their study, the researchers will apply their technique to autopsied brain samples from people with and without Alzheimer's disease. By comparing mitochondrial DNA patterns in these samples, the team hopes to determine whether people with Alzheimer's experience a general increase in DNA mutants throughout the brain—or whether such mutants arise only in brain regions affected by dementia pathology. Dr. Sondheimer's group will then look for areas in the brain tissues where oxidative stress has occurred. Oxidative stress is the damage caused to brain cells by toxic oxygen molecules, and it is closely linked to dysfunctional mitochondria. By locating areas of oxidative stress, the team can better pinpoint where mitochondrial mutants exist in the Alzheimer's brain.
Dr. Sondheimer and colleagues hope to clarify whether or not changes in mitochondrial DNA are responsible for initiating Alzheimer's disease. Their own hypothesis argues that DNA changes are induced during Alzheimer's and can help promote cognitive decline. The researchers could verify this hypothesis if they show that mitochondrial DNA mutants arise only in brain regions where Alzheimer's damage has already occurred. Such findings could help future studies develop more precise Alzheimer's therapies that target mitochondrial function.