How SORLA protects against Alzheimer's disease

November 7, 2017, Sanford-Burnham Prebys Medical Discovery Institute
Huaxi Xu, Ph.D., Professor, Neuroscience and Aging Research Center. Credit: Sanford Burnham Prebys Medical Discovery Institute (SBP)

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 Medicine, could inform novel treatment strategies.

"We found that a protein called SORLA directly limits the ability of amyloid beta, the toxic protein that causes Alzheimer's, to trigger the destruction of neuronal connections," says Huaxi Xu, Ph.D., professor and the Jeanne and Gary Herberger Leadership Chair of SBP's Neuroscience and Aging Research Center. (SORLA stands for sortilin-related receptor with LDLR class A repeats.) "This is actually the third way that SORLA has been shown to defend against neurodegeneration."

"It's becoming increasingly clear that the SORLA gene has a major influence on Alzheimer's development—more and more Alzheimer's-associated mutations in the SORLA gene are being discovered," Xu adds. "Our findings help explain why they are so important."

SORLA is one of many genes in which mutations are associated with increased risk of Alzheimer's, which affects 5.5 million people in the U.S. The biggest risk factor is age—as the average life expectancy increases, the number of people with Alzheimer's is expected to almost triple by 2050.

Alzheimer's begins when amyloid beta aggregates into small clusters outside neurons. Those clusters, called oligomers, induce toxic signaling that damages the connections between synapses so that neurons can no longer talk to one another. Synapse loss is the reason Alzheimer's patients develop memory problems.

Xu and his collaborators suspected that SORLA—a trafficking protein that shuttles molecules between cellular compartments—might help protect against amyloid beta induced toxic signaling based on their prior observations. SORLA has already been shown to counteract production of amyloid beta and eliminate it from the space around neurons.

Xu's team recently reported that SORLA physically interacts with EphA4, one of the receptors through which amyloid beta provokes synaptic dysfunction. (EphA4 exists primarily to control the wiring of neuronal networks as the brain develops and regulate the behavior of synapses in the adult brain.)

In this study, Xu's team established that SORLA could mitigate the toxic EphA4 signaling caused by amyloid beta. They also showed that increasing levels of SORLA in mice reduced cognitive impairments caused by beta.

"These observations suggest that early-stage Alzheimer's could be treated with drugs that increase levels of SORLA, or that enhance its interaction with EphA4," comments Xu. "We're currently searching for drugs that have either of these effects.

"The researchers also found that EphA4 is over-activated in brain tissue from Alzheimer's patients, and that over-activation correlates with decreased binding to SORLA, demonstrating the relevance of this discovery to human disease.

"Our study also provides support to explore EphA4 inhibitors as Alzheimer's therapeutics," Xu notes. "There's preclinical data from disease models suggesting they have some efficacy."

"SORLA is becoming a hot topic in Alzheimer's research. No other protein has yet been found to influence Alzheimer's pathogenesis in so many ways. And it may do even more—we plan to explore whether it modulates other cell surface receptors such as the cellular prion protein and the NMDA receptor."

Explore further: SORLA controls insulin signaling to promote obesity in mice

Related Stories

SORLA controls insulin signaling to promote obesity in mice

June 20, 2016
Large-scale genetic studies have linked variations in genes and proteins to an increased risk for developing obesity. Determining how these variations alter metabolism to increase body mass may lead to the identification ...

Insulin-sensitive fat leads to obesity

June 21, 2016
SORLA is a protein that influences the balance of metabolic processes in adipose tissue, a particular form of fat. Too much of it makes fat cells overly sensitive to insulin, which leads them to break down less fat. SORLA ...

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 ...

'Pac-Man' gene implicated in Alzheimer's disease

July 26, 2016
A gene that protects the brain from the harmful build-up of amyloid-beta, one of the causative proteins implicated in Alzheimer's disease, has been identified as a new target for therapy by NeuRA researchers.

Gene variant protecting against Alzheimer's disease decreases plasma beta-amyloid levels

June 20, 2017
New research from the University of Eastern Finland shows that the APP gene variant protecting against Alzheimer's disease significantly decreases plasma beta-amyloid levels in a population cohort. This is a very significant ...

Hyperactive neurons may be culprit in Alzheimer's

January 13, 2016
A long-term reduction in neuronal activity reduces amyloid plaques associated with Alzheimer's disease, Yale University researchers have found. The study, using mouse models of Alzheimer's, found the opposite is also true—triggering ...

Recommended for you

Neurons with good housekeeping are protected from Alzheimer's

December 17, 2018
Some neurons in the brain protect themselves from Alzheimer's with a cellular cleaning system that sweeps away toxic proteins associated with the disease, according to a new study from Columbia University and the University ...

Growing a brain: Two-step control mechanism identified in mouse stem cells

December 17, 2018
Scientists have identified two distinct control mechanisms in the developmental transition of undifferentiated stem cells into healthy brain cells. This fundamental research using mice may inform regenerative medicine treatments ...

Does diabetes damage brain health?

December 14, 2018
(HealthDay)—Diabetes has been tied to a number of complications such as kidney disease, but new research has found that older people with type 2 diabetes can also have more difficulties with thinking and memory.

Amyloid pathology transmission in lab mice and historic medical treatments

December 13, 2018
A UCL-led study has confirmed that some vials of a hormone used in discontinued medical treatments contained seeds of a protein implicated in Alzheimer's disease, and are able to seed amyloid pathology in mice.

Study links slowed brainwaves to early signs of dementia

December 13, 2018
To turn back the clock on Alzheimer's disease, many researchers are seeking ways to effectively diagnose the neurodegenerative disorder earlier.

New discoveries predict ability to forecast dementia from single molecule

December 11, 2018
Scientists who recently identified the molecular start of Alzheimer's disease have used that finding to determine that it should be possible to forecast which type of dementia will develop over time—a form of personalized ...

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.