Fighting Alzheimer's disease with protein origami

July 12, 2013
Figure 1: Prefoldin protein expression (green) in mice with high levels of amyloid-β in their brains (cell nuclei stained in blue). Credit: 2013 American Chemical Society

Alzheimer's disease is a progressive degenerative brain disease most commonly characterized by memory deficits. Loss of memory function, in particular, is known to be caused by neuronal damage arising from the misfolding of protein fragments in the brain. Now, a group of researchers led by Mizuo Maeda of the RIKEN Bioengineering Laboratory, and including researchers from the Laboratory for Proteolytic Neuroscience at the RIKEN Brain Science Institute, has found that the human protein prefoldin can change the way these misfolded protein aggregates form and potentially reduce their toxic impact on the brains of Alzheimer's patients.

The formation of insoluble fibril aggregates of the protein amyloid-? has been identified as a key mechanism responsible for memory loss in Alzheimer's patients. These fibrils are toxic to neurons, and finding a means of preventing their formation represents a key strategy in the development of a therapy for the disease. Recent studies suggest methods that alter the mechanism of amyloid-? aggregates could offer a promising approach.

Prefoldin is a involved in preventing the clumping of misfolded proteins and helping misfolded proteins return to their normal shape. The researchers found that amyloid-? molecules incubated with even just a small amount of human prefoldin underwent a change in aggregation behavior—they instead formed into small, soluble oligomer clumps. The observations suggest that human prefoldin interacts with amyloid-? molecules to alter their binding properties.

As in the brain, amyloid-? fibrils also kill neurons in cell culture. Using neurons from the brains of mice, the researchers showed that the amyloid-? oligomers formed in the presence of human prefoldin induced less than amyloid-? fibrils. Prefoldin expression actually increases in the brains of mice with high levels of amyloid-? (Fig. 1), suggesting that the upregulation of prefoldin expression might be a response mechanism used by the brain to protect itself from the toxic effects of amyloid-? fibrils.

Many researchers currently believe that amyloid-? oligomers are themselves a toxin that induces neuronal dysfunction. The present results, however, suggest that certain types of oligomers may in fact be less toxic than other conformations of amyloid-? aggregates. Increasing the expression of human prefoldin in the brain may therefore increase the proportion of less toxic amyloid-? aggregates, presenting a potential means of fighting the disease.

"Our findings may also apply to various other neurological diseases caused by protein misfolding, such as prion disease, Huntington's disease and Parkinson's disease," explains Tamotsu Zako from the research team.

Explore further: New Alzheimer's research suggests possible cause: The interaction of proteins in the brain

More information: Sörgjerd, K. et al. Human prefoldin inhibits amyloid-? (A?) fibrillation and contributes to formation of non-toxic A? aggregates. Biochemistry 52, 3532–3542 (2013). dx.doi.org/10.1021/bi301705c

Related Stories

New Alzheimer's research suggests possible cause: The interaction of proteins in the brain

June 19, 2013
For years, Alzheimer's researchers have focused on two proteins that accumulate in the brains of people with Alzheimer's and may contribute to the disease: plaques made up of the protein amyloid-beta, and tangles of another ...

Researchers investigate mechanism of Alzheimer's therapy

July 8, 2013
Researchers at the University of Kentucky Sanders-Brown Center on Aging, led by faculty member Donna Wilcock, have recently published a new paper in the Journal of Neuroscience detailing an advance in treatment of Alzheimer's ...

Discovery sheds light on why Alzheimer's meds rarely help

July 1, 2013
New research reveals that the likely culprit behind Alzheimer's disease has a different molecular structure than current drugs' target—perhaps explaining why these medications produce little improvement in patients.

A molecular chain reaction in Alzheimer's disease

May 29, 2013
Researchers at Lund University in Sweden have identified the molecular mechanism behind the transformation of one of the components in Alzheimer's disease. They identified the crucial step leading to formations that kill ...

Researchers investigate the amyloid-beta peptide behind Alzheimer's

November 5, 2012
Using solid-state nuclear magnetic resonance (NMR) spectroscopy, researchers at Luleå University of Technology in collaboration with Warwick University in the UK for the first time in the world managed to analyse hydrogen ...

Brain enzyme is double whammy for Alzheimer's disease

August 20, 2012
The underlying causes of Alzheimer's disease are not fully understood, but a good deal of evidence points to the accumulation of β-amyloid, a protein that's toxic to nerve cells. β-amyloid is formed by the activity ...

Recommended for you

Noninvasive eye scan could detect key signs of Alzheimer's years before patients show symptoms

August 17, 2017
Cedars-Sinai neuroscience investigators have found that Alzheimer's disease affects the retina—the back of the eye—similarly to the way it affects the brain. The study also revealed that an investigational, noninvasive ...

Could olfactory loss point to Alzheimer's disease?

August 16, 2017
By the time you start losing your memory, it's almost too late. That's because the damage to your brain associated with Alzheimer's disease (AD) may already have been going on for as long as twenty years. Which is why there ...

New Machine Learning program shows promise for early Alzheimer's diagnosis

August 15, 2017
A new machine learning program developed by researchers at Case Western Reserve University appears to outperform other methods for diagnosing Alzheimer's disease before symptoms begin to interfere with every day living, initial ...

Brain scan study adds to evidence that lower brain serotonin levels are linked to dementia

August 14, 2017
In a study looking at brain scans of people with mild loss of thought and memory ability, Johns Hopkins researchers report evidence of lower levels of the serotonin transporter—a natural brain chemical that regulates mood, ...

Alzheimer's risk linked to energy shortage in brain's immune cells

August 14, 2017
People with specific mutations in the gene TREM2 are three times more likely to develop Alzheimer's disease than those who carry more common variants of the gene. But until now, scientists had no explanation for the link.

Scientists reveal role for lysosome transport in Alzheimer's disease progression

August 7, 2017
Researchers from Yale University School of Medicine have discovered that defects in the transport of lysosomes within neurons promote the buildup of protein aggregates in the brains of mice with Alzheimer's disease. The study, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.