A team led by Associate Professor Guo Baosheng and Professor Jiang Qing from the School of Medicine at Nanjing University, along with Professor Shi Yun, has uncovered a novel regulatory mechanism where bone-brain axis metabolism disruption accelerates cognitive impairment in pathological conditions. This marks the first international discovery that osteoporosis can hasten cognitive decline, offering new insights for clinical treatments of conditions like Alzheimer's disease. The research findings were recently published online in Nature Metabolism.
In the aging process and progression of Alzheimer's disease, bone cells' specific secretion of sclerostin protein passes through the blood-brain barrier, suppressing the central nervous system's Wnt pathway and upregulating BACE1 expression. Image provided by the research team.
The study found that bone-derived sclerostin can inhibit the Wnt/β-catenin pathway through the blood-brain barrier, exacerbating cognitive decline during aging and Alzheimer's disease progression. These findings not only reveal the mechanism of cognitive impairment in Alzheimer's disease and other diseases due to metabolic disruption in the bone-brain axis but also enrich the theoretical basis of organ cross-regulation, providing new insights for the clinical treatment of Alzheimer's disease and other neurodegenerative diseases.
"We often observe in clinical practice that elderly individuals, especially women, experience bone fractures due to osteoporosis, accompanied by cognitive decline," explained Jiang Qing. "When the body suffers from osteoporosis, the bones release a substance, namely sclerostin protein. Blood tests of patients showed an increase in sclerostin components, and in cerebrospinal fluid tests, the concentration of sclerostin protein also significantly increased. In response to this phenomenon, we immediately initiated further research."
"Our research findings suggest that for healthy elderly individuals, the entry of sclerostin protein into the brain can impair cognitive function, and for elderly dementia patients, it can further worsen their condition," Jiang Qing stated. Recent studies have found a significant correlation between cognitive impairment during the progression of Alzheimer's disease and abnormalities in bone metabolism. However, whether osteoporosis affects the human brain, damaging our cognitive function, and whether there is an inherent relationship between them, has never had a clear explanation internationally, and our research findings are the first to discover this.
In fact, besides its roles in movement and support, the skeleton acts as a non-classical endocrine organ, playing a crucial role in maintaining organism homeostasis. The research team found that in hospitalized patients with normal cognitive function, the concentration of sclerostin in cerebrospinal fluid significantly increased with age. Additionally, the Wnt/β-catenin signal plays a crucial role in the pathogenesis of Alzheimer's disease, validating related conclusions.
Professor Lorenz Hofbauer from the Department of Endocrinology at Dresden University of Technology commented in a concurrent research brief, "This is an excellent paper, providing convincing experimental evidence elucidating the role and mechanism of bone-derived sclerostin protein in neurodegenerative diseases, demonstrating the potential of using sclerostin-neutralizing antibodies for treating severe osteoporosis as a therapy for Alzheimer's disease."
Doctoral students Shi Tianshu, Shen Siyu, and Shi Yong from Nanjing Medical University School of Medicine are co-first authors of the paper, with Guo Baosheng, Jiang Qing, and Shi Yun as corresponding authors.
Related paper information: https://doi.org/10.1038/s42255-024-00989-x
