Neurodegenerative conditions, including Alzheimer’s disease, are frequently characterized by the aberrant transformation of tau, a protein intrinsically vital for the structural integrity of nerve cells. Under physiological circumstances, tau plays a crucial role in stabilizing microtubules, which are essential filamentous structures responsible for maintaining neuronal morphology and functionality. However, in the context of disease, tau undergoes pathological modifications, aggregating into toxic formations that disrupt the intricate neural circuitry it would normally help to preserve. Researchers at Sanford Burnham Prebys have identified a protein that appears to offer a protective shield against this tau-induced damage, a discovery that could pave the way for novel therapeutic strategies targeting tau-related neurodegenerative disorders.
The research, published in the journal Science Advances, highlights the significant protective functions of a protein known as sorting-related receptor with A-type repeats, or SORLA. This finding offers a compelling new avenue for intervention, suggesting that therapeutic approaches could be developed to bolster this natural defense mechanism, thereby mitigating the detrimental consequences of diseases associated with tau pathology.
Tau proteins are ubiquitously distributed throughout the brain and the broader nervous system, where their primary function is to provide mechanical support to neurons and the complex networks they constitute. The pathological cascade in Alzheimer’s disease and other tauopathies involves the accumulation of tau proteins within the confines of nerve cells. These abnormal aggregates, commonly referred to as tau tangles, are strongly correlated with a decline in cognitive abilities, profound disturbances in brain function, and ultimately, neuronal death.
Previous investigations, spanning approximately the last two decades, have amassed substantial evidence from multiple research groups, including the laboratory that conducted this latest study, demonstrating SORLA’s capacity to suppress a key hallmark of Alzheimer’s disease: the generation and accumulation of amyloid-beta. However, the extent to which SORLA influences tau tangles, which represent the other significant pathological feature of Alzheimer’s, remained largely unexplored.
To elucidate the potential role of SORLA in tau pathology, the research team employed a sophisticated mouse model. They crossbred mice engineered to exhibit elevated levels of human SORLA with mice that naturally develop tau tangles, accompanied by brain atrophy and cognitive impairments. This dual-model approach provided an ideal platform to investigate whether increased SORLA expression could modulate tau accumulation and the subsequent neurodegenerative processes.
The experimental results were highly encouraging, indicating that elevated SORLA levels actively interfered with several critical mechanisms implicated in the formation of tau tangles and the progression of neurodegeneration. Specifically, SORLA was found to reduce the excessive addition of phosphate groups to tau proteins, a process known as hyperphosphorylation, which is a crucial step in tau’s pathological transformation. Furthermore, SORLA limited the capacity of misfolded tau proteins to act as "seeds," initiating the recruitment of additional tau proteins and thereby fostering the growth of larger, more toxic aggregates.
The beneficial effects of SORLA extended beyond its direct impact on tau. Mice exhibiting higher SORLA expression maintained healthier synapses, the critical junctions where neurons communicate with each other, and demonstrated enhanced preservation of synaptic plasticity. Synaptic plasticity refers to the brain’s remarkable ability to adapt and modify these neural connections, a process fundamental to learning and memory. The lead author of the study, Huijie Huang, a staff scientist in the Huang lab, stated that upregulating SORLA effectively suppressed the adverse effects observed in tauopathies. The observation of reduced brain atrophy and diminished tau accumulation was particularly exciting for the researchers.
To further understand the consequences of SORLA’s presence or absence, the researchers also investigated mice genetically engineered to lack the Sorl1 gene, which is responsible for producing SORLA. These animals experienced the antithesis of the protective effects seen in mice with elevated SORLA. Tim Huang, the senior and corresponding author of the manuscript, noted that the deletion of SORLA production exacerbated the harmful effects characteristic of tauopathies, underscoring the protein’s critical protective role.
To dissect the molecular underpinnings of SORLA’s differential effects based on its abundance, the research team utilized advanced sequencing and mapping technologies. These cutting-edge methods allowed them to measure protein levels and gene activity within individual cells, while also providing spatial information about the location of RNA and proteins within brain tissue.
The comprehensive analysis revealed that increased SORLA expression effectively prevented detrimental alterations in protein production at synapses. It also suppressed the activity of several other biological pathways that are known to contribute to the progression of tauopathy. Notably, higher SORLA levels also attenuated disease-associated patterns of gene activity within glial cells. Glial cells, often considered the support staff of the nervous system, perform a multitude of essential functions, including neuronal support, maintenance of the brain’s internal milieu, and orchestrating the response to injury and damage.
One particularly significant finding, as highlighted by Huijie Huang, was the observed upregulation of a specific member of the plexin-B family of receptors in the absence of SORLA. This observation opens up intriguing therapeutic possibilities, as Tim Huang pointed out that there are existing drugs that specifically target this class of receptors. The potential exists to repurpose these drugs to address tau-related dementia disorders by targeting the overactivation of glial cells and, in doing so, potentially reversing some of the pathological features of tauopathies.
The researchers are now embarking on a more granular examination of how different types of brain cells respond to fluctuations in SORLA levels. Their future work includes the innovative approach of grafting human neurons or glial cells into mouse brains. This strategy will allow them to study the impact of various SORLA mutations within the context of a living disease environment, providing insights that are more directly relevant to human pathology, given the inherent differences between mouse and human cells.
Further investigations are anticipated to elucidate the precise mechanisms by which SORLA confers protection against toxic tau tangles and to determine whether this protective capacity can be therapeutically amplified. This line of inquiry may also prove instrumental in identifying existing pharmaceutical agents that could be repurposed for the treatment of Alzheimer’s disease and other tau-driven dementias.
The study involved a collaborative effort with additional authors including 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, all from Sanford Burnham Prebys. Qiang Xiao from The Scripps Research Institute also contributed to the research. The study received vital financial support from the National Institutes of Health, the National Cancer Institute, and the National Institute on Aging.
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