Arizona Researchers Say Genetic Changes Could Help Spot Alzheimer’s Disease Early

Published: Monday, November 21, 2016 - 8:52am
Updated: Monday, November 21, 2016 - 3:33pm
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(Photo courtesy of Arizona State University)
Mitochondria are membrane-bound organelles present in eukaryotic cells. Their essential role is to supply cells with energy in the form of ATP. Mitochondrial dysfunction is implicated in a range of diseases, including Alzheimer's.

Researchers at Arizona State University’s Biodesign Institute and the Banner Sun Health Research Institute have isolated genetic changes that could help stop Alzheimer’s disease in its earliest stages and serve as possible treatment targets.

The study found that declines in gene expression related to the cellular “power plants” known as mitochondria occurred in subjects as young as their early 30s.

“By the time 70 years old comes, you start to see the full effects of the disease, but the processing really starts early in our 30s,” said Diego Mastroeni, assistant professor at the Biodesign Institute and lead author on the paper.

The Institute for Memory Impairments and Neurological Disorders at University of California, Irvine, also contributed to the study, which was published in the October 25 edition of Alzheimer’s & Dementia.

Alzheimer’s disease is the foremost cause of dementia, and the sixth leading cause of death, in the United States. Its symptoms include progressive memory loss, confusion, mood and personality changes, and decline in physical and mental functions. It has no known cure.

Experts are still struggling to isolate the disease’s causes and to track its progress. Often, a definitive diagnosis must await an autopsy, which can reveal telltale neurofibrillary tangles and beta-amyloid plaques in the deceased person’s brain. But research shows that, long before they develop tangles or plaques, brains with Alzheimer’s disease acquire glitches in their cells’ power plants — the mitochondria — that impede cellular energy production.  

Mitochondria are oval structures within cells that release energy from sugars and fats using oxygen and enzymes. How many of these organelles occur in a cell varies from zero (in red blood cells) to hundreds (in liver and muscle cells). Mitochondria play a number of other key roles in cells, such as handling oxidative stress and regulating cell death.

Medical research has linked mitochondrial glitches to a number of diseases, including Huntington’s disease, Parkinson’s disease and Lou Gehrig's disease (amyotrophic lateral sclerosis), as well as diabetes, stroke and obesity-related pathologies.

“It’s pretty common. It seems to be an overarching mechanism in a lot of these neurodegenerative diseases,” said Mastroeni.

Similarly, decline in the expression of key mitochondrial genes could forge the first links in Alzheimer’s disease’s dire chain of progression.

The genes in question affect oxidative phosphorylation (OXPHOS), the final stage in mitochondria’s chemical breakdown of sugars and ensuing release of energy. Some OXPHOS-related genes come from mitochondria themselves — mitochondria have their own DNA — but occur in the nucleus.

“Within each complex, there’s maybe one or two genes that are made inside of the mitochondria themselves, and then the remaining are all being pulled from the nucleus,” said Mastroeni.

To assess the source of these brain cell “power outages,” researchers compared mitochondrial and nuclear gene expression in persons with Alzheimer’s disease to those without. They evaluated expression by looking at mRNA in the hippocampus, a portion of the brain associated with memory.

The authors found that the changes occurred entirely within the cell’s nucleus and not in the mitochondrial DNA.

“It’s just the nuclear-encoded ones that are affected. The mitochondria-encoded genes themselves? They seem to be fine. They seem to be making their own proteins no problem," said Mastroeni. “When they require new proteins to be made from the nucleus — they’re calling the nucleus, saying, ‘We need this protein to be made’ — they’re not getting there. The message is not there.”

The authors suggest that restoring expression of affected genes, or improving function in mitochondria via other means, could offer a way to delay the disease’s progression. According to Mastroeni, drugs currently under development, such as analogs of coenzyme q10, an essential antioxidant, could achieve boost mitochondrial energy production.

“The processes are going on right now. So if we could slow it down — say, by 10 years or so — it would be quite significant," Mastroeni said.

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