Injury to mitochondria — tiny powerhouses inside cells that provide them with energy — triggers events that occur early in Alzheimer's disease and may offer a promising target for treatment.

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Researchers suggest that injury to mitochondria may drive Alzheimer's disease.

So concludes a new study published in the journal Alzheimer's & Dementia that shows how oligomeric amyloid beta —a highly toxic protein — disrupts mitochondria.

The study also reveals how a pre-treatment might protect human brain cells from such damage.

"Mitochondria," says lead author Dr. Diego Mastroeni, an assistant professor at Arizona State University in Tempe, "are the major source of energy in brain cells and deficiencies in energy metabolism have been shown to be one of the earliest events in Alzheimer's disease pathobiology."

Alzheimer's is a devastating disease that destroys brain tissue and robs people of their ability to think, remember, make decisions, socialize, and live independently.

It is the most common form of dementia and the sixth leading cause of death in the United States, where more than 5 million people have the condition.

The burden of Alzheimer's disease in the U.S. is growing as the population ages. The cost of Alzheimer's and other dementias is set to rise from $259 billion to $1.1 trillion between 2017 and 2050.

As it progresses, the disease changes the biology and chemistry of the brain causing nerve cells, or neurons, to perish and tissue to shrink.

There is currently no cure or effective treatment that significantly slows the progress of Alzheimer's disease.

Signs of early tissue change are known to be in train before behavioral symptoms of Alzheimer's emerge; however, despite some strong theories, the exact causes remain a mystery.

Amyloid beta and Alzheimer's disease

A dominant theory about the origins of Alzheimer's proposes that accumulation of sticky protein fragments called amyloid beta set off the chain of events in the brain that leads to the disease.

The main evidence to support this amyloid theory is that brain autopsies of people who died with Alzheimer's disease have two distinctive types of abnormal protein accumulations: tangles inside cells and plaques between cells.

These hallmarks of Alzheimer's have been found mainly in the hippocampus, the neocortex, and other parts of the brain that sit below the cortex and are important for thinking, memory, and learning.

However, as research has probed more deeply into the disease and its possible causes, problems with the amyloid theory have emerged, say the authors of the new study.

One problem concerns inconsistencies in the evidence. For example, some studies have reported that, despite the heavy presence of amyloid plaques in their brains, some older patients showed no measurable deficits in thinking and memory, while other patients with severe Alzheimer's-like symptoms have shown very little buildup of abnormal amyloid protein.

Another reason to question the amyloid theory is that experimental drugs that target amyloid as a way to treat Alzheimer's have shown disappointing results in clinical trials and have failed to halt the decline.

These questions and problems have led researchers to argue that plaques and tangles likely emerge in later stages of Alzheimer's and that other triggers are involved.

A role for mitochondria?

Mitochondria are tiny compartments inside cells in which oxygen and nutrients transform into adenosine triphosphate (ATP), which is the main source of fuel for cellular activity.

"Decades of research" have revealed that these cellular powerhouses differ between Alzheimer's brains and healthy brains.

This has led to the view that mitochondria play an important role in Alzheimer's, not only as contributors but also as drivers of disease.

The current debate ranges from suggesting that amyloid beta causes mitochondrial dysfunction to proposing that a "cascade" of mitochondrial changes "hierarchically supersedes" the development of amyloid beta.

Another argument in the debate proposes that, in Alzheimer's disease, a "highly toxic" form of amyloid beta — known as oligomeric amyloid beta —accelerates the mitochondrial decline that occurs naturally with age.

The new study, which examines the impact of oligomeric amyloid beta on mitochondria in brain cells, provides fresh evidence in this direction.

Evidence of disruption to mitochondria

For their study, Dr. Mastroeni and colleagues extracted pyramidal neurons from the hippocampus in the brains of patients who had died of Alzheimer's disease.

Pyramidal neurons have been described as the "movers and shakers" of the brain and are important for cognitive processing. Brain-wasting diseases such as Alzheimer's are known to disproportionately kill these cells.

When they studied the hippocampal pyramidal neurons, the researchers found evidence — in the form of reduced expression of many mitochondrial genes — to suggest that their mitochondria had been disrupted by oligomeric amyloid beta.

They found the same reduced expression of mitochondrial genes occurred when they exposed cells from a human neuroblastoma cell line to the toxic protein.

Other types of cell — such as astrocyte and microglia cells — extracted from the hippocampus of the same Alzheimer's disease-affected brains, did not show evidence of impaired mitochondria. Astrocyte and microglia cells provide support such as maintaining chemical balance and supplying nutrients.

Pre-treatment may protect neurons

In another series of experiments, the researchers pre-treated human neurons in the laboratory with a compound that is structurally similar to CoQ10, which is known to boost ATP and limit oxidative stress, another process that can degrade mitochondria.

When they exposed the pre-treated neurons to oligomeric amyloid beta, they showed reduced signs of mitochondrial deterioration. They suggest that this result could pave the way to new treatments for Alzheimer's disease.

"This study reinforces the toxicity of oligomeric amyloid beta on neuronal mitochondria and stresses the importance for protective compounds to protect the mitochondria from oligomeric amyloid beta toxicity."

Dr. Diego Mastroeni