Alzheimer’s disease and several other neurodegenerative diseases are associated with harmful changes in the tau protein, which normally helps support the internal structures of nerve cells. Under healthy conditions, tau stabilizes microtubules, filament-like structures that help maintain neuron shape and function. But when we get sick, tau can twist into toxic tangles that interfere with brain circuits that would normally help maintain it.
Researchers at Sanford Burnham Prebys announced on July 17, 2026, scientific progress It is thought that another protein may help protect the brain from this damage. Their findings raise the possibility that future treatments can strengthen this natural defense and reduce the harmful effects of tau-related diseases.
How tau tangles affect the brain
Tau is normally present throughout the brain and nervous system and helps maintain the structure of neurons and the networks they form.
In Alzheimer’s disease and other tauopathies, tau proteins begin to accumulate within nerve cells. These abnormal clumps, known as tau tangles, are associated with cognitive decline, disrupted brain function, and neuron death.
A new study investigated the protective role of a protein called sorting-associated receptor with A-type repeats (SORLA).
“Over the past 15 to 20 years, considerable data has emerged from our lab and other groups showing that SORLA can suppress the production and accumulation of amyloid beta, which is one of the hallmarks of Alzheimer’s disease,” said Dr. Timothy Huang, assistant professor at the Sanford Burnham Prebys Center for Neurological Diseases.
“However, little was known about whether SORLA affects tau tangles, which is reflected on the other side of the Alzheimer’s disease coin.”
Testing SORLA in a mouse model
To investigate, researchers crossed mice that produced high levels of human SORLA with mice that developed tau tangles, brain atrophy, and cognitive impairment. This combined model allowed the team to study whether additional SORLA could influence tau accumulation and subsequent damage.
The results showed that high SORLA levels interfere with several processes involved in tau tangle formation and neurodegeneration. SORLA reduced the excessive addition of phosphate groups to tau, a process known as hyperphosphorylation. It also limited the ability of malformed tau to act as a “seed” that collects more tau proteins and builds larger clumps.
The protective effect extended beyond tau itself. Mice with more SORLA had healthier synapses, the communication points between neurons, and were shown to have better preserved synaptic plasticity (the brain’s ability to strengthen or adjust their connections).
“Upregulating SORLA can suppress the negative effects seen in tauopathies,” said Huijie Huang, Ph.D., a staff scientist in the Fan lab at Sanford Burnham Prebys and lead author of the study.
“We found that there was less brain atrophy and tau accumulation, which was a very interesting result.”
What happened when SORLA was removed?
Some people carry mutations that disrupt Sorl1, the gene that provides instructions for making SORLA. To compare the effects of excess SORLA with the complete absence of the protein, the researchers also studied mice genetically modified to lack Sorl1.
Those animals experienced the opposite result.
“When we removed the ability to produce SORLA proteins, we found that the opposite was true,” said Tim Huang, senior and corresponding author of the paper. “SORLA deficiency exacerbated the deleterious effects observed in tauopathies.”
Changes across neurons and glial cells
To understand why SORLA had such disparate effects depending on its abundance, the team used several advanced sequencing and mapping techniques. These approaches measured protein levels and gene activity in individual cells, while also showing where RNA and proteins were located within brain tissue.
The analysis revealed that increasing SORLA prevented deleterious changes in protein production at synapses. It also inhibited several other biological pathways associated with tauopathy progression.
Higher SORLA levels also decreased disease-associated gene activity patterns in glial cells. These cells perform many important functions, including supporting neurons, maintaining the brain environment, and responding to injury.
“One particularly remarkable finding that we can make is that members of the plexin B family of receptors are upregulated in the absence of SORLA,” said Huijie Huang.
“We have unique drugs that can target this class of receptors and may have applications in tau-related dementia diseases,” said Tim Huang. “One possible future direction is to repurpose these drugs to target glial cell hyperactivation and perhaps reverse some of the tauopathy phenotypes.”
A potential path to new treatments
The researchers now want to take a closer look at how individual types of brain cells respond when SORLA levels rise or fall. Their planned research involves transplanting human neurons and glial cells into mouse brains so that they can study different SORLA mutations in a live disease setting.
“Mouse cells and human cells are different,” says Tim Huang. “Since we are looking at human disease, it will be more informative if we can observe SORLA modulation and dysfunction in the context of human cells within the diseased brain environment.”
Future research may determine how SORLA protects the brain from toxic tau tangles and whether that protection can be enhanced therapeutically. The study could also help researchers identify existing drugs that can be repurposed for Alzheimer’s disease and other dementias caused by tau.
Other authors include:
Christina Huang Xi, Wenqi Yang, Juan C. Piña-Crespo, Jay Bhatnagar, Julian Curatolo, Ravi Murad, Palak Shah, Alex Campos, Alexandra Houser, Rebecca A. Pollitt, Jau Van Vo, Tongmei Zhang, Shenjie Fung, and Kevin Y. Yip at Sanford Burnham Prebys.
Qiang Xiao of Scripps Research Institute
This research was supported by the National Institutes of Health, the National Cancer Institute, and the National Institute on Aging.
