Researchers Study Mitochondrial Variation in Predisposition to Alzheimer’s Disease

Douglas C. Wallace, PhD, demonstrates the critical role that the mitochondria play in a variety of commonly diagnosed human diseases.

By Barbara Drosey

A Children's Hospital of Philadelphia geneticist who founded the field of mitochondrial medicine is studying how defects in mitochondrial energy production (MEP) could contribute to neurological diseases such as Alzheimer's, Parkinson's, autism, and schizophrenia.

The National Institute on Aging awarded a grant to Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenetic Medicine and the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases, to lead the collaborative project with colleagues at CHOP and the University of Pennsylvania.

Demonstrating the critical role that the mitochondria play in a variety of commonly diagnosed human diseases is a decades-long theme of Dr. Wallace's work. Given that the brain is the organ most reliant on MEP, it follows that chronic mitochondrial deficiency should cause neurological disease. Furthermore, mitochondrial function declines with age, accounting for the delayed onset and progressive course of neurological diseases. Since mitochondrial dysfunction is systemic, identification of mitochondrial dysfunction in muscle or blood could lead to early recognition of age-related diseases such as Alzheimer's disease and permit early interventions that prevent the disease later in life.

"We're in a position to make a real difference by developing novel, preventive therapies that may prove beneficial in treating Alzheimer's disease by treating the mitochondria," Dr. Wallace said. "Beyond Alzheimer's disease, this logic applies to diabetes, cardiovascular disease, renal function, retinal degeneration, and more."

Mitochondrial Dysfunction's Predictive Potential

Amyloid β peptides form the plaques that appear in the brains of individuals with Alzheimer's disease and related dementia and, for more than a decade, the assumption was that amyloid β plaques were the cause of Alzheimer's dementia. But Dr. Wallace believes that amyloid β plaques are a symptom, not the cause of Alzheimer's disease; therefore, efforts to remove β amyloid from the brain has not prevented Alzheimer's dementia. Dr. Wallace's team has shown that chronic mitochondria dysfunction and the mitochondrial production of toxic oxygen radicals (mitochondrial reactive oxygen species, mROS) contribute to Alzheimer's disease and that amyloid β production is one of the consequences of the mitochondrial defect. Chronic mitochondrial dysfunction and mROS production ultimately kills the nerve cells which results in memory loss and cognitive impairment. Mitochondrial dysfunction also activates the immune system causing inflammation.

Each human cell contains multiple mitochondria and each mitochondrion contains its own mitochondrial DNA (mtDNA) that code for critical genes for MEP, the process called oxidative phosphorylation. Hence, the mtDNA can be envisioned as the wiring diagram of the mitochondrial power plant.

The human cell is like a city with a sufficient number of power plants to provide backup power in times of high energy demand. Each mitochondrial power plant has its own mtDNA, which is prone to damage by the mROS produced during MEP. Over time, the mtDNAs of different mitochondria become damaged, taking that mitochondrion's energy production offline. As more and more mtDNAs become damaged, the total cellular energy production declines until it falls below the minimum energy output for that cell to adequately perform its function within the organ.

Since this process happens concurrently in all the cells in a tissue, the cumulative energy decline results in progressive tissue and organ dysfunction and ultimately failure, a process Dr. Wallace likens to a metropolitan brownout. Since the brain has the highest energy demand, it is often the first organ to be affected by this age-related mitochondrial decline. However, other organs with high-mitochondrial energy demand, such as the heart and kidney, can also be affected, exhibiting symptoms even though the parallel process is occurring throughout the body. This enables Dr. Wallace to assay for mitochondrial dysfunction in other parts of the body as a predictor of what's going on in the brain.

Detection of the premature decline in the body's MEP can then be used as an indicator of the predisposition to neurological diseases such as Alzheimer's. Consequently, the research team is developing noninvasive, preclinical tests to assess mitochondria function, in order to identify individuals with potential risk for Alzheimer's disease. Methods in development include evaluating oxygenated and deoxygenated hemoglobin using a near-infrared light as an individual performs simple exercises, and isolating chemical molecules released during exhalation.

The team is also developing therapies to enhance cellular energy production, decrease mROS toxicity, and modulate the inflammatory responses of the immune system. Using a combination of preclinical testing and preventive mitochondrial therapy, the team hopes to decrease the risk of Alzheimer's dementia later in life.

Joining Dr. Wallace, who is also a Penn professor of Pathology and Laboratory Medicine, in this work is Wayne W. Hancock, MBBS, PhD, FRCPA, chief, Division of Transplant Immunology at CHOP and professor of Pathology and Laboratory Medicine at Penn, and Frederick "Chris" Bennett, MD, research faculty in the Department of Child and Adolescent Psychiatry and Behavioral Sciences at CHOP, and assistant professor of Psychiatry at Penn.