How SORLA Protects Against Alzheimer’s Disease

Source: Sanford Burnham Prebys Medical Discovery Institute

Summary: Researchers have identified a new protective function for a brain protein which is genetically linked to Alzheimer’s. Study findings could lead to new therapeutic approaches to combat neurodegenerative diseases.

Alzheimer’s is a neurodegenerative disease which affects nearly 5.5 million people in the U.S and age is being the biggest risk factor. Amyloid beta is a toxic protein form as the main component in the amyloid plaques found in the brains of Alzheimer patients. It triggers the destruction of neuronal connections between the synapses in the brain. Synapse loss is the main reason Alzheimer patients develop memory problems. Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new protective function for this amyloid beta. They found a protein called SORLA (sortilin-related receptor with LDLR class A repeats) which directly limits the ability of amyloid beta. SORLA gene has a major influence on the development of Alzheimer’s disease as more and more Alzheimer’s-associated mutations are being discovered in the SORLA gene. The findings were published in the Journal of Experimental Medicine.

SORLA (sortilin-related receptor with LDLR class A repeats)

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

The research team reported that SORLA physically interacts with EphA4, a receptor through which amyloid beta provokes synaptic dysfunction. SORLA has the ability to mitigate the toxic EphA4 signaling caused by amyloid beta. Increased levels of SORLA reduced cognitive impairments in mice. They also found that EphA4 is over-activated in brain tissue from Alzheimer’s patients which led to its decreased binding to SORLA. These studies suggest that Alzheimer’s at an early stage could be treated with drugs which increase the levels of SORLA or enhance its interaction with EphA4.

Prof. Huaxi Xu said, “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 amyloid beta receptors such as the cellular prion protein and the NMDA receptor.”

More Information: Timothy Y. Huang et al, “SORLA attenuates EphA4 signaling and amyloid β–induced neurodegeneration”, Journal of Experimental Medicine (2017). DOI: 10.1084/jem.20171413


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