In Mouse Study, Plaques Linked to Alzheimer’s Nearly Wiped Out
Researchers at Ohio State University have discovered that eliminating an enzyme from mice with symptoms of Alzheimer’s disease leads to a 90 percent reduction in the compounds responsible for forming the plaques linked to the disease.
The compounds are amyloid beta or A-beta peptides, according to the researchers; peptides are proteins, but shorter in length.
When A-beta peptides accumulate in excessive amounts in the brain, they can form plaques, which are a hallmark of Alzheimer’s disease.
“These mice are models for the most aggressive form of Alzheimer’s disease and produce the highest amount of A-beta peptides. This 90 percent reduction is the biggest drop in A-beta levels that has been reported so far by treating animal models with drugs or genetic manipulations,” said Sung Ok Yoon, Ph.D., associate professor of molecular & cellular biochemistry at Ohio State University and lead author of the study.
The key to reducing A-beta peptides was the elimination of an enzyme called jnk3, according to the study.
This enzyme stimulates a protein that produces A-beta peptides, suggesting that when jnk3 activities are high, A-beta peptide production increases, which increases the chances of their accumulation and formation into plaques.
Jnk3 is an enzyme that modifies its target proteins, changing the protein properties. Amyloid precursor protein (APP), which produces A-beta peptides, was already known to be modified in Alzheimer’s disease brains. Yoon and her colleagues also found that jnk3 modifies APP, which leads to stimulation of A-beta peptide production.
While Alzheimer’s affects more than 5 million Americans, its cause remains unknown. Although scientists have not yet determined whether A-beta peptides present in plaques cause Alzheimer’s disease or form as a consequence of the disease, the plaques are linked to progressive cognitive decline.
In this study, Yoon and her colleagues deleted jnk3 genetically from mice carrying the mutations found in early-onset Alzheimer’s disease patients.
In six months, A-beta peptide production was lowered by 90 percent, with a 70 percent reduction seen at 12 months in these mice.
When the researchers saw that eliminating jnk3 dramatically lowered A-beta peptides, they also looked for effects on cognitive function at 12 months in the mice.
They found that cognitive function improved significantly, reaching 80 percent of normal, while cognitive function in disease model mice was 40 percent of normal.
The number of brain cells, or neurons, in the Alzheimer’s disease mice was also increased by deleting jnk3, reaching 86 percent of the value in normal mice, while the neuron numbers were only 74 percent in Alzheimer’s model mice.
The scientists also examined whether patterns of RNA expression in the mouse brains were changed when jnk3 was deleted. This pattern tells scientists whether cells are behaving as expected, explained the researchers, who said the results were a big surprise. Expression of genes that are necessary for new protein production, or synthesis, was significantly reduced in the Alzheimer’s model brains compared to normal mouse brains.
“A lot of neurons had shut off their protein production. And when we deleted jnk3, the neurons’ overall protein production came very close to normal levels,” Yoon said.
According to the research team, experiments in neuron cultures also showed that A-beta peptides turn off new protein production by activating another enzyme called AMP kinase (AMPK). AMPK is normally activated when cells are starved of nutrients, such as right before a meal. For that reason, AMPK is a popular target in diseases associated with the body’s use of glucose and fats for metabolism, such as Type 2 diabetes, the researchers explained.
The researchers observed that, once activated, AMPK eventually silenced a sequence of chemical reactions called the mTOR pathway, which controls new protein synthesis in a variety of cell types. This phenomenon launches a stress response in the endoplasmic reticulum (ER), which is the protein synthesis machine present in every single cell.
“The interesting thing is, it had already been published that when ER stress is induced, that could activate jnk3,” Yoon said.
That led the researcher and her colleagues to propose a model to describe their hypothesis. Continual jnk3 activation by ER stress allows a detrimental cycle to start, and this cycle gets stronger over time, she said, explaining that an as-yet unidentified physiological problem increases jnk3 activity, which leads to initial production of A-beta peptides from APP.
These peptides stimulate the AMPK enzyme, which blocks new protein production by the mTOR pathway. The lowered protein production leads to ER stress, and this increases jnk3 activities. As at the start, the increased jnk3 activities lead to production of more A-beta, adding “more push” to the cycle, Yoon explained.
“So, around and around and around it goes, ever more strongly. These results suggest that jnk3 is the key perpetuating the cycle,” she said.
To test the hypothesis, the researchers treated live mouse brain tissues with one drug that blocks the mTOR pathway or another drug that induces ER stress. Both treatments dramatically increased A-beta peptide production within nine hours, but only when jnk3 was present, she said. When examining human data, the researchers observed that Alzheimer’s disease brain tissue showed a prominent elevation of ER stress.
Though a missing link remains — the pathological condition that produces the stress in the first place — Yoon said the demonstration that A-beta peptides block new protein production reveals new ways of thinking about Alzheimer’s disease treatment.
“The fact that we found that protein synthesis is hugely affected by Alzheimer’s disease opens up a door to let us try a variety of drugs that are already developed for other chronic progressive diseases that share this commonality of affected protein production,” Yoon said.
Yoon also hopes to test whether small-molecule jnk3 inhibitors could potentially improve cognitive function in mice with Alzheimer’s disease.
The research is published in the journal Neuron.
Source: Ohio State University
Wood, J. (2012). In Mouse Study, Plaques Linked to Alzheimer’s Nearly Wiped Out. Psych Central. Retrieved on April 25, 2015, from http://psychcentral.com/news/2012/09/06/in-mouse-study-plaques-linked-to-alzheimers-nearly-wiped-out/44181.html