### Breakthrough in Alzheimer's Research at Tsinghua University: First Revealing of Pathogenic Protein Structure On the morning of July 3, 2014, Tsinghua University announced a significant breakthrough by Professor Yigong Shi, a renowned structural biologist and member of the Chinese Academy of Sciences. Shi's research group successfully revealed the detailed three-dimensional structure of the human γ-secretase complex, which is directly linked to the onset of Alzheimer's disease (commonly known as senile dementia). This groundbreaking achievement was published online in the prestigious British journal *Nature* on June 29, 2014. #### Key Events and Findings The γ-secretase complex is a critical enzyme involved in the degradation of waste proteins in cell membranes. It functions akin to a "garbage shredder" within the cell, breaking down these proteins into smaller fragments for reabsorption and reuse by the body. However, abnormalities in the γ-secretase complex's activity, particularly its abnormal cleavage of the amyloid precursor protein (APP), lead to the overproduction of Aβ42 peptides, which aggregate to form amyloid plaques. These plaques are a hallmark of Alzheimer's disease and are believed to contribute significantly to cognitive decline and memory loss. For decades, researchers worldwide have been striving to determine the high-resolution structure of the γ-secretase complex. Prior to Shi's work, the best resolution achieved by foreign scientists was 12 Å (angstroms). Shi's team, using cryo-electron microscopy, managed to achieve a resolution of 4.5 Å, providing an unprecedented level of detail into the structure of this complex. This advancement is crucial for understanding the mechanism of γ-secretase and the pathogenesis of Alzheimer's disease. #### Significance and Impact Professor Shi emphasized that this discovery is the most significant breakthrough of his career. While other studies have made progress in understanding the functional aspects of Alzheimer's disease, this is the first time the spatial structure of the γ-secretase complex has been elucidated. He likened the previous research to viewing a bun from 100 meters away, whereas his team's work is akin to viewing it from 5 meters. The ultimate goal is to achieve even finer resolution, akin to viewing a bun from 10 centimeters away. #### Alzheimer's Disease: A Growing Global Health Concern Alzheimer's disease is a fatal neurodegenerative disorder characterized by progressive cognitive impairment, with memory loss being its most prominent symptom. The disease primarily affects individuals over 65 years old, although early-onset cases do occur. With increasing life expectancy, the incidence of Alzheimer's is on the rise. Notable figures such as former U.S. President Ronald Reagan and former British Prime Minister Margaret Thatcher have suffered from this condition. In China, approximately 5 million people are estimated to have Alzheimer's, accounting for one-quarter of the global patient population. According to data, around 26 million people worldwide had Alzheimer's in 2006, and it is projected that by 2050, one in every 85 people will be affected by the disease. Alzheimer's is a significant financial burden in developed countries, and despite extensive research, there are currently no effective treatments to halt or reverse its progression. Clinically, the focus is on symptom management, such as improving memory, reducing harmful substances, and treating insomnia. #### Clinical Applications and Future Prospects While the revelation of the γ-secretase complex's structure is a major step forward in the foundational understanding of Alzheimer's disease, its practical application in clinical settings remains distant. Dr. Baoquan Min, a neurologist at Xuanwu Hospital, highlighted that the current treatment landscape for Alzheimer's is limited to symptomatic relief. There are no direct, effective drugs available to treat the disease, and the existing treatments aim to slow its progression by addressing specific symptoms like memory loss and sleep disorders. Dr. Min noted that while the pathogenesis of Alzheimer's is well understood, the development of effective therapeutic drugs has lagged behind. The detailed structure of the γ-secretase complex, as revealed by Professor Shi's team, opens new avenues for drug design and therapeutic strategies. However, translating this knowledge into clinical practice will require further research and development. #### About Professor Yigong Shi Yigong Shi is a native of Zhengzhou, Henan, and is internationally recognized for his contributions to structural biology. He is a foreign member of both the U.S. National Academy of Sciences and the American Academy of Arts and Sciences, and a member of the Chinese Academy of Sciences. Shi joined Tsinghua University as a professor in February 2008 and has been serving as the Dean of the School of Life Sciences since September 28, 2009. His accolades include the 2010 Raymond and Beverly Sackler International Prize in Biophysics and the 2014 Gregori Aminoff Prize, which he is the first Chinese recipient to win. The Aminoff Prize is a highly esteemed international award presented by the King of Sweden. ### Conclusion The work by Professor Yigong Shi and his team at Tsinghua University represents a monumental achievement in the field of Alzheimer's research. By unveiling the detailed structure of the γ-secretase complex, they have provided crucial insights that could pave the way for the development of more effective treatments. However, the journey from basic research to clinical application is long and complex, and ongoing efforts will be necessary to translate these findings into tangible benefits for patients and their families. This breakthrough underscores the importance of continued investment in scientific research and collaboration across international boundaries to tackle one of the most pressing health challenges of our time.