Recent research published in Science Advances has found that increasing the levels of a specific protective protein in the brain can reduce the toxic buildup of tau, a protein linked to Alzheimer’s disease. The findings suggest that boosting this protein helps preserve brain connections and reduces harmful inflammation. These discoveries offer new insights into how the brain defends itself against neurodegenerative conditions and point toward potential new therapeutic targets.
Alzheimer’s disease and several other neurodegenerative conditions are characterized by the abnormal accumulation of specific proteins in the brain. One of these proteins is tau, which normally helps stabilize the internal framework of nerve cells. In diseases known as tauopathies, tau proteins become misshapen and clump together to form toxic structures called tangles. These tangles disrupt cellular communication, eventually leading to cognitive decline and the death of brain cells.
Past genetic studies have linked variations in a specific gene, known as SORL1, to an increased risk of developing late-onset Alzheimer’s disease. This gene provides the instructions for making a protein called SORLA. This protein operates as a cellular receptor involved in sorting and transporting materials within the biological compartments of cells. Previous work established that the protein helps reduce the accumulation of amyloid-beta, another toxic protein central to Alzheimer’s disease.
Despite this knowledge about amyloid-beta, very little was known about whether this receptor also influenced the formation of tau tangles inside living organisms. To address this gap in knowledge, researchers aimed to uncover exactly how this sorting protein interacts with tau pathology. The scientists wanted to observe its concurrent effects on different types of brain cells in a living system. Lead authors Huijie Huang and Timothy Y. Huang, both affiliated with the Sanford Burnham Prebys Medical Discovery Institute, guided the research team to determine if altering the levels of this protein would change the progression of tau-related brain damage.
The researchers developed specialized breeding programs using mice to examine the protein’s effects on brain health. They bred a specific strain of mice genetically engineered to produce abnormally high levels of the human SORLA protein. These mice were then crossbred with PS19 mice, a widely used animal model that expresses a mutated human tau protein. The PS19 mice naturally develop tau tangles, experience brain shrinkage, and show signs of severe brain inflammation by the time they are about eight to nine months old.
By comparing these crossbred mice with standard PS19 mice, the authors could observe the impact of abundant sorting proteins on disease progression. The team analyzed brain tissues from mice at varying ages, including three, seven, nine, and eleven months old, to track pathological changes over time. They utilized a combination of advanced laboratory techniques to measure these biological changes. These techniques included proteomics to study large-scale protein expression and single-nucleus RNA sequencing to map gene activity in individual cells.
The team also used specialized electrical recordings in brain slices to measure long-term potentiation, a process that reflects the strengthening of synapses. The results provided evidence that extra SORLA protein protected the aging mouse brains from several destructive processes. In the nine-month-old mice, high levels of the sorting protein significantly reduced the excessive addition of phosphate molecules to tau. This chemical alteration, called hyperphosphorylation, is the primary trigger that causes tau to tangle.
The extra protein also prevented the abnormal widening of the brain’s fluid-filled spaces, a condition called ventricle dilation that indicates widespread brain tissue loss. In addition, the mice with extra sorting proteins maintained better synaptic plasticity compared to the standard tauopathy mice. Synaptic plasticity is the ability of brain connections to adapt and strengthen over time, which is fundamental for learning and memory.
Beyond preserving synapses, the abundant protein suppressed the overactivation of glial cells. Glial cells are supportive cells in the brain that can cause damaging inflammation when they become hyperactive in response to disease. The proteomics analysis revealed that the extra protein normalized the levels of specific molecules like ApoE and C1q. In a diseased state, these molecules tend to drive the targeted destruction of healthy synapses by immune cells.
The single-nucleus RNA sequencing provided a highly detailed map of gene activity across different brain cell types. This cellular mapping showed that abundant SORLA reversed many of the disease-associated gene signatures in the PS19 mice. The analysis identified the involvement of a cellular communication pathway known as semaphorin-plexin signaling. Specifically, the receptor proteins Plexin B1 and Plexin B2 were found in high amounts in the inflamed glial cells of the diseased mice, but their levels returned to near-normal when extra sorting protein was present.
To confirm their findings, the scientists conducted a complementary experiment by engineering mice that entirely lacked the SORLA protein. When these knockout mice were crossed with the PS19 tau model, the absence of the sorting protein worsened the brain damage. The knockout mice showed more severe tau clumping and an increased ability for the toxic tau to spread to other cells. They also exhibited even higher levels of glial cell inflammation and Plexin B receptors compared to mice with normal protein levels.
Further tests using cultured brain cells in laboratory dishes helped explain how the protein might be exerting its protective effects. The scientists exposed isolated nerve cells and microglia, the brain’s primary immune cells, to toxic tau clumps. Cells with artificially high levels of the sorting protein were much more effective at capturing the toxic tau from their surroundings. Once absorbed, the protein helped transport the tau into lysosomes, which function as the cellular waste disposal system, thereby preventing the tau from escaping and causing cellular damage.
Several limitations shape the interpretation of these findings. The use of global genetic modifications affects the entire animal, making it difficult to pinpoint whether the protective effects originate primarily from nerve cells or from the supportive glial cells. Because the sorting protein is present in multiple types of brain tissue, the observed benefits likely result from a complex interaction between these different cell populations. The exact molecular mechanism by which the receptor binds to tau and influences its cellular transport also remains partially unresolved.
Another limitation is that the PS19 animal model only exhibits tau accumulation. It lacks the amyloid-beta plaques that also define human Alzheimer’s disease. As a result, this model does not fully replicate the complex environment of a human brain experiencing full-blown Alzheimer’s disease. The researchers note that short-term adjustments to this protein in isolated human cells might yield different results compared to the long-term genetic changes tested in aging mice.
Future research is planned to address these gaps and build upon the current findings. The authors intend to use more advanced animal models that incorporate both amyloid-beta and tau pathologies to better mimic human neurodegeneration. They also hope to study genetically modified mice where the sorting protein is removed only from specific cell types, which would clarify the distinct roles of neurons and glia. The team plans to eventually graft human brain cells into mouse models to observe how human-specific cellular environments react to changes in this receptor protein.
The study, “SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain,” was authored by 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, and Timothy Y. Huang.