New player in Alzheimer's disease pathogenesis identified

November 14, 2017, Sanford-Burnham Prebys Medical Discovery Institute
PET scan of a human brain with Alzheimer's disease. Credit: public domain

Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have shown that a protein called membralin is critical for keeping Alzheimer's disease pathology in check. The study, published in Nature Communications, shows that membralin regulates the cell's machinery for producing beta-amyloid (or amyloid beta, Aβ), the protein that causes neurons to die in Alzheimer's disease.

"Our results suggest a new path toward future treatments for Alzheimer's disease," says Huaxi Xu, Ph.D., the Jeanne and Gary Herberger Leadership Chair of SBP's Neuroscience and Aging Research Center. "If we can find molecules that modulate membralin, or identify its role in the cellular disposal machinery known as the endoplasmic reticulum-associated degradation (ERAD) system, this may put the brakes on neurodegeneration."

ERAD is the mechanism by which cells get rid of proteins that are folded incorrectly in the ER. It also controls the levels of certain mature, functional proteins. Xu's team found that one of the fully formed, working proteins that ERAD regulates is a component of an enzyme called that generates Aβ.

This discovery helps fill in the picture of how Alzheimer's disease, an incredibly complicated disorder influenced by many genetic and environmental factors. No therapies have yet been demonstrated to slow progression of the disease, which affects around 47 million people worldwide. Until such drugs are developed, patients face a steady, or sometimes rapid, decline in memory and reasoning.

Memory loss in Alzheimer's results from the toxic effects of Aβ, which causes connections between neurons to break down. Aβ is created when gamma secretase cuts the into smaller pieces. While Aβ is made in all human brains as they age, differences in the rate at which it is produced and eliminated from the brain and in how it affects neurons, means that not everyone develops dementia.

"We were interested in membralin because of its genetic association with Alzheimer's, and in this study we established the connection between membralin and Alzheimer's based on findings from the laboratory of a former colleague at SBP, Professor Dongxian Zhang," Xu explains. "That investigation showed that eliminating the gene for membralin leads to rapid motor neuron degeneration, but its cellular function wasn't clear."

Using proteomics, microscopic analysis, and functional assays, the group provided definitive evidence that membralin functions as part of the ERAD system. Later, they found that membralin-dependent ERAD breaks down a protein that's part of the gamma secretase enzyme complex, and that reducing the amount of membralin in a mouse model of Alzheimer's exacerbates neurodegeneration and memory problems.

"Our findings explain why mutations that decrease membralin expression would increase the risk for Alzheimer's," Xu comments. "This would lead to an accumulation of gamma secretase because its degradation is disabled, and the gamma-secretase complex would then generate more Aβ. Those mutations are rare, but there may be other factors that cause neurons to make less membralin."

Xu and colleagues also observed lower levels of membralin, on average, in the brains of patients with Alzheimer's than in unaffected individuals, demonstrating the relevance of their findings to humans.

"Previous studies have suggested that ERAD contributes to many diseases where cells become overwhelmed by an irregular accumulation of proteins, including Alzheimer's," says Xu. "This study provides conclusive, mechanistic evidence that ERAD plays an important role in restraining Alzheimer's . We now plan to search for compounds that enhance production of membralin or the rate of ERAD to test whether they ameliorate pathology and cognitive decline in models of Alzheimer's. That would further support the validity of this mechanism as a drug target."

Explore further: How SORLA protects against Alzheimer's disease

More information: Bing Zhu et al, ER-associated degradation regulates Alzheimer's amyloid pathology and memory function by modulating γ-secretase activity, Nature Communications (2017). DOI: 10.1038/s41467-017-01799-4

Related Stories

How SORLA protects against Alzheimer's disease

November 7, 2017
Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new protective function for a brain protein genetically linked to Alzheimer's. The findings, published in the Journal of Experimental ...

One step closer toward a treatment for Alzheimer's disease?

October 18, 2017
Scientists at the Massachusetts General Hospital (MGH), in collaboration with colleagues at the University California, San Diego (UCSD), have characterized a new class of drugs as potential therapeutics for Alzheimer's disease ...

Novel perspectives on anti-amyloid treatment for the prevention of Alzheimer's disease

July 27, 2017
For decades researches have been investigating the underlying foundations of Alzheimer's disease to provide clues for the design of a successful therapy. This week, VIB/KU Leuven scientists have published breakthrough insights ...

Researchers work to block harmful behavior of key Alzheimer's enzyme

February 25, 2016
Enzymes rarely have one job. So, attempts to shut down the enzyme that causes the hallmarks of Alzheimer's disease often mean side effects, because these therapies prevent the enzyme from carrying out many other functions. ...

New insight on why people with Down syndrome invariably develop Alzheimer's disease

October 23, 2014
A new study by researchers at Sanford-Burnham Medical Research Institute reveals the process that leads to changes in the brains of individuals with Down syndrome—the same changes that cause dementia in Alzheimer's patients. ...

Research identifies a molecular basis for common congenital brain defect

December 13, 2016
Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have discovered a molecular cause of hydrocephalus, a common, potentially life-threatening birth defect in which the head is enlarged due to excess fluid ...

Recommended for you

A new approach for finding Alzheimer's treatments

September 11, 2018
Considering what little progress has been made finding drugs to treat Alzheimer's disease, Maikel Rheinstädter decided to come at the problem from a totally different angle—perhaps the solution lay not with the peptide ...

Study prevents cognitive decline in older blacks with memory loss

September 10, 2018
With nearly twice the rate of dementia as whites, blacks are at a higher risk for developing diseases like Alzheimer's, but there has been little research on how to reduce this racial health disparity. A new study in black ...

Excessive daytime sleepiness linked with brain protein involved in Alzheimer's disease

September 6, 2018
Analysis of data captured during a long-term study of aging adults shows that those who report being very sleepy during the day were nearly three times more likely than those who didn't to have brain deposits of beta amyloid, ...

Study shows how exercise generates new neurons, improves cognition in Alzheimer's mouse

September 6, 2018
A study by a Massachusetts General Hospital (MGH) research team finds that neurogenesis -inducing the production of new neurons—in the brain structure in which memories are encoded can improve cognitive function in a mouse ...

Novel strategy shows promise for earlier detection of Alzheimer's disease

September 4, 2018
Finding an effective way to identify people with mild cognitive impairment who are most likely to go on to develop Alzheimer's disease has eluded researchers for years. But now, a team of researchers led by David Loewenstein, ...

Dementia symptoms peak in winter and spring, study finds

September 4, 2018
Adults both with and without Alzheimer's disease have better cognition skills in the late summer and early fall than in the winter and spring, according to a new study published this week in PLOS Medicine by Andrew Lim of ...

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.