Recent research published in scientific progress They found that increasing levels of certain protective proteins in the brain can reduce the toxic buildup of tau, a protein associated with Alzheimer’s disease. The findings suggest that increasing this protein can help maintain brain connectivity and reduce harmful inflammation. These findings provide new insights into how the brain protects against neurodegenerative conditions and point to potential new therapeutic targets.
Alzheimer’s disease and several other neurodegenerative conditions are characterized by an abnormal accumulation of certain 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, the tau protein deforms and clumps together to form toxic structures called tangles. These tangles disrupt cellular communication, ultimately leading to cognitive decline and brain cell death.
Previous genetic studies have linked mutations in a particular gene, known as SORL1, to an increased risk of developing late-onset Alzheimer’s disease. This gene provides instructions for making a protein called SORLA. This protein functions as a cellular receptor involved in the sorting and transport of substances within the biological compartments of the cell. Previous studies have shown that this protein helps reduce the buildup of amyloid beta, another toxic protein central to Alzheimer’s disease.
Despite this knowledge about amyloid beta, little was known about whether this receptor also influences the formation of tau tangles in vivo. To address this knowledge gap, the researchers aimed to uncover exactly how this sorting protein interacts with tau pathology. Scientists wanted to observe its simultaneous effects on different types of brain cells within a biological system. Lead authors Huijie Huang and Timothy Y. Huang, both of the Sanford Burnham Prebys Medical Discovery Institute, guided the research team to determine whether altering levels of this protein alters the progression of tau-related brain damage.
The researchers developed a special breeding program in mice to examine the effects of this protein on brain health. They bred a particular strain of mice that had been genetically engineered to produce abnormally high levels of the human SORLA protein. These mice were then crossed with PS19 mice, a widely used animal model that expresses a mutated human tau protein. By the time PS19 mice are about 8 to 9 months old, they spontaneously develop tau tangles, their brains shrink, and they show signs of severe brain inflammation.
By comparing these crossbred mice with standard PS19 mice, the authors were able to observe the effects of the abundant sorting proteins on disease progression. The research team analyzed brain tissue from mice at different ages, including 3, 7, 9, and 11 months old, to track pathological changes over time. They utilized a combination of advanced experimental techniques to measure these biological changes. These techniques include proteomics to study large-scale protein expression and single-nuclear RNA sequencing to map gene activity in individual cells.
The research team also used specialized electrical recordings of brain slices to measure long-term potentiation, a process that reflects the strengthening of synapses. The results provide evidence that extra SORLA protein protects the aging mouse brain from several destructive processes. In 9-month-old mice, high levels of the sorting protein significantly reduced the excessive addition of phosphate molecules to tau. This chemical change, called hyperphosphorylation, is the main trigger for tau tangles.
The extra protein also prevented the abnormal expansion of fluid-filled spaces in the brain, a condition called ventricular dilatation, which indicates extensive brain tissue loss. Additionally, mice with additional sorting proteins maintained better synaptic plasticity compared to standard tauopathy mice. Synaptic plasticity is the ability of brain connections to adapt and strengthen over time, and is the basis of learning and memory.
The abundant protein not only preserved synapses but also suppressed glial cell hyperactivation. Glial cells are supporting cells in the brain, and when overactivated in response to disease, they can cause harmful inflammation. Proteomic analysis revealed that the extra proteins normalized the levels of certain molecules such as ApoE and C1q. In disease states, these molecules tend to cause targeted destruction of healthy synapses by immune cells.
Single-nuclear RNA sequencing has provided highly detailed maps of gene activity across different types of brain cells. This cellular mapping showed that abundant SORLA reverses many of the disease-associated gene signatures in PS19 mice. This analysis identified the involvement of a cellular communication pathway known as semaphorin-plexin signaling. Specifically, the receptor proteins plexin B1 and plexin B2 were detected in high amounts in the inflamed glial cells of affected mice, but their levels returned to near normal in the presence of the extra sorting proteins.
To confirm their findings, the scientists performed complementation experiments in mice that were completely deficient in the SORLA protein. When these knockout mice were crossed with the PS19 tau model, brain damage was exacerbated by the lack of the sorting protein. The knockout mice showed more severe tau aggregation and an increased ability for toxic tau to spread to other cells. They also showed higher levels of glial inflammation and plexin B receptors compared to mice with normal protein levels.
Further tests using brain cells grown in laboratory dishes helped explain how this protein exerts its protective effects. The scientists exposed isolated nerve cells and microglia, the brain’s main immune cells, to toxic tau clumps. Cells containing artificially high levels of sorting proteins were much more effective at capturing toxic tau from their surroundings. Once absorbed, this protein helps transport tau to lysosomes, which act as the cell’s waste disposal system, thereby preventing it from escaping and causing cell damage.
Several limitations shape the interpretation of these findings. The use of widespread genetic modifications affects the whole animal, making it difficult to determine whether the protective effects originate primarily from neurons or from supportive glial cells. Because sorting proteins are present in multiple types of brain tissue, the observed benefits likely result from complex interactions between these different cell populations. The precise molecular mechanisms by which the receptor binds tau and affects its cellular trafficking also remain partially unresolved.
Another limitation is that the PS19 animal model only shows tau accumulation. It lacks amyloid-beta plaques, which are also a hallmark of Alzheimer’s disease in humans. As a result, this model does not fully reproduce the complex environment of a human brain with full-blown Alzheimer’s disease. The researchers note that short-term modulation of this protein in isolated human cells may yield different results than testing long-term genetic changes in aging mice.
Future research is planned to address these gaps and build on current findings. The authors plan to use more advanced animal models that incorporate both amyloid beta and tau pathology to better mimic human neurodegeneration. They also hope to study genetically modified mice that remove sorting proteins only from specific cell types, which will reveal the different roles of neurons and glia. The researchers eventually plan to transplant human brain cells into mouse models to see how the unique human cellular environment responds to changes in this receptor protein.
The study, “Upregulation of SORLA suppresses pathological effects in the brains of aged tauopathy mice,” was conducted 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.
