Alzheimer’s disease and several other neurodegenerative disorders are linked to a damaging change in tau, a protein that normally helps support the internal structure of nerve cells. Under healthy conditions, tau stabilizes microtubules, the filament-like structures that help maintain neuronal shape and function. In disease, however, tau can twist into toxic tangles that interfere with the brain circuits it would normally help preserve.
Researchers at Sanford Burnham Prebys reported on July 17, 2026, in Science Advances that another protein may help protect the brain from this damage. Their findings raise the possibility that future therapies could strengthen this natural defense and reduce the harmful effects of tau-related disease.
How Tau Tangles Damage the Brain
Tau is normally found throughout the brain and nervous system, where it helps maintain the structure of neurons and the networks they form.
In Alzheimer’s disease and other tauopathies, tau proteins begin accumulating inside nerve cells. These abnormal clumps, known as tau tangles, are associated with cognitive decline, disrupted brain function, and the death of neurons.
The new research examined the protective role of a protein called sorting-related receptor with A-type repeats (SORLA).
“In the last 15 or 20 years, considerable data has come out from our lab and other groups showing that SORLA can suppress one of the hallmarks of Alzheimer’s disease — amyloid-beta generation and accumulation,” said Timothy Huang, PhD, assistant professor in the Center for Neurologic Diseases at Sanford Burnham Prebys.
“Very little was known, however, about whether SORLA affected the tau tangles reflected on the other side of the coin in Alzheimer’s disease.”
Testing SORLA in a Mouse Model
To investigate, the researchers crossbred mice that produce elevated levels of human SORLA with mice that develop tau tangles, brain atrophy and cognitive deficits. This combined model allowed the team to study whether additional SORLA could influence tau accumulation and the damage that follows.
The results showed that higher SORLA levels interfered 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 “seeds” that recruit more tau proteins and build larger clumps.
The protective effects extended beyond tau itself. Mice with more SORLA retained healthier synapses, the communication points between neurons, and showed better preservation of synaptic plasticity, the brain’s ability to strengthen or adjust those connections.
“When you upregulate SORLA, you can suppress the negative effects found in tauopathies,” said Huijie Huang, PhD, a staff scientist in the Huang lab at Sanford Burnham Prebys and lead author of the study.
“We found there was less brain atrophy and less tau accumulation, which was very exciting to see.”
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 a complete lack of the protein, the researchers also studied mice genetically modified to lack Sorl1.
Those animals experienced the reverse outcome.
“The opposite turned out to be true when we deleted the ability to produce SORLA proteins,” said Tim Huang, senior and corresponding author of the manuscript. “A lack of SORLA exacerbated the harmful effects observed in tauopathies.”
Changes Across Neurons and Glial Cells
To determine why SORLA had such different effects depending on its abundance, the team used several advanced sequencing and mapping methods. 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 harmful changes in protein production at synapses. It also suppressed several other biological pathways associated with the progression of tauopathy.
Higher SORLA levels also reduced disease-related patterns of gene activity in glial cells. These cells perform many essential functions, including supporting neurons, maintaining the brain’s environment, and responding to damage.
“One particularly notable finding that we can build on is the upregulation of a member of the plexin-B family of receptors in the absence of SORLA,” said Huijie Huang.
“There are unique drugs that can target this class of receptors that we may be able to apply to tau-related dementia disorders,” said Tim Huang. “One potential future direction is to repurpose these drugs to target overactivation of glial cells and perhaps reverse some of the phenotypes in tauopathies”
A Possible Path Toward New Treatments
The researchers now want to examine more closely how individual types of brain cells respond when SORLA levels rise or fall. Their planned work includes grafting human neurons or glial cells into mouse brains so they can study different SORLA mutations in a living disease environment.
“Mouse cells and human cells are different,” said Tim Huang. “Because we’re looking at human disease, it’s more informative if we can observe the modulation and dysfunction of SORLA in the context of a human cell inside of a diseased brain environment.”
Future studies could clarify how SORLA protects the brain from toxic tau tangles and whether that protection can be enhanced therapeutically. The work may also help researchers identify existing drugs that could be repurposed for Alzheimer’s disease and other dementias driven by tau.
Additional authors include:
Christina Huan Shi, Wenqi Yang, Juan C. Piña-Crespo, Jay Bhatnagar, Julian Curatolo, Rabi Murad, Palak Shah, Alex Campos, Alexandra Houser, Rebecca A. Porritt, Giau Van Vo, Tongmei Zhang, Shengjie Feng and Kevin Y. Yip at Sanford Burnham Prebys
Qiang Xiao at The Scripps Research Institute
The study was supported by the National Institutes of Health, National Cancer Institute and National Institute on Aging.