Could This Brain Protein Be the Key to Combating Alzheimer's?
A naturally occurring brain protein may help defend against one of the most damaging processes involved in Alzheimer's disease, according to new research that found boosting the protein reduced toxic tau buildup, brain shrinkage and loss of connections between nerve cells in mice. The study, published July 17 in Science Advances by researchers at Sanford Burnham Prebys, focused on a protein called SORLA, which scientists say appears to act as a protective mechanism against tau pathology—a hallmark of Alzheimer's disease and other forms of dementia known as tauopathies. Tau normally helps maintain the structure and function of neurons by stabilizing microtubules, the internal scaffolding that supports nerve cells. But in Alzheimer's disease, tau proteins can accumulate inside neurons and form abnormal clumps known as tau tangles. These tangles are associated with cognitive decline, disrupted brain function and neuron death. Researchers found that mice engineered to produce higher levels of human SORLA developed less tau accumulation and experienced less brain atrophy than mice with tau pathology alone. "We found there was less brain atrophy and less tau accumulation, which was very exciting to see," Huijie Huang, PhD, a staff scientist at Sanford Burnham Prebys and lead author of the study, said in a statement. ...The team created the mouse model by crossbreeding mice that produce elevated levels of human SORLA with mice that develop tau tangles, brain atrophy and cognitive deficits. The resulting animals allowed researchers to investigate whether increasing SORLA could affect tau-related brain damage. Their findings suggest SORLA interferes with several key processes involved in the development of tau tangles. Higher levels of the protein reduced tau hyperphosphorylation—the excessive addition of phosphate groups linked to abnormal tau behavior—and limited the ability of malformed tau proteins to act as "seeds" that recruit additional tau and form larger clumps. The benefits extended beyond tau itself. Mice with elevated SORLA retained healthier synapses, the communication points between neurons, and maintained better synaptic plasticity, the brain's ability to strengthen and adapt those connections over time. "When you upregulate SORLA, you can suppress the negative effects found in tauopathies," Huijie Huang said. The researchers also examined the opposite scenario by studying mice genetically engineered to lack the Sorl1 gene, which provides instructions for making SORLA. Those animals experienced worse outcomes. "The opposite turned out to be true when we deleted the ability to produce SORLA proteins," senior author Timothy Huang said. "A lack of SORLA exacerbated the harmful effects observed in tauopathies." Using advanced techniques that measured protein levels and gene activity in individual cells while mapping RNA and proteins within brain tissue, the researchers found that increasing SORLA also prevented harmful changes in protein production at synapses and suppressed several biological pathways linked to disease progression. Higher levels of SORLA also reduced disease-associated gene activity in glial cells, which support neurons, maintain the brain's environment and respond to injury. The study identified another potentially important clue. Researchers found increased activity of a member of the plexin-B family of receptors when SORLA was absent. Because drugs already exist that target this class of receptors, the team suggested they could potentially be repurposed in the future to reduce harmful glial-cell activity in tau-related dementias. Dr. Dayan Goodenowe, a neuroscientist and founder and CEO of Prodrome Sciences who was not involved in the study, told Newsweek that tau remains a critical focus of Alzheimer's research because its spread closely mirrors disease progression. "Tau pathology is one of the defining features of Alzheimer's disease because it closely tracks the progression of neurodegeneration, and it's been very clear in my research that as the disease advances, neurofibrillary tangles become more widespread throughout the brain...and that makes tau an important marker of disease severity," he said. Goodenowe said the study is notable because it highlights the brain's own protective systems rather than focusing solely on damaging processes. "This study is encouraging because it reminds us that the brain has its own protective biology. Alzheimer's is not simply a process of accumulating damage ...we often forget that there are also natural systems working to preserve neuronal health," he said. He added that understanding why these protective mechanisms work in some individuals but fail in others could be just as important as understanding the disease itself. "I believe discoveries like this shift the conversation in an important direction...rather than focusing only on removing harmful proteins after damage has occurred, we should also understand and strengthen the biological systems that naturally protect neurons throughout life. That may ultimately prove to be a more effective long-term strategy," he said. Still, Goodenowe cautioned that promising laboratory findings must ultimately prove they can help patients. "Now...to the challenges... in my view, biology is only the beginning and every single promising laboratory discovery must still demonstrate meaningful clinical benefit in people," he said. The Sanford Burnham Prebys team now plans to study how different brain cell types respond to changes in SORLA levels, including experiments that place human neurons and glial cells into mouse brains. The researchers hope future work will reveal more about how SORLA protects against toxic tau tangles and whether its effects can eventually be harnessed to treat Alzheimer's disease and other tau-related dementias. Reference: Huijie Huang, 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, Qiang Xiao, Tongmei Zhang, Shengjie Feng, Kevin Y. Yip, Timothy Y. Huang. SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain. Science Advances, 2026; 12 (29) DOI: 10.1126/sciadv.aed6825 Contact Newsweek editors on this story: Kara Dolman and Emma Lee-Sang
