Xin Wang’s team identified noncanonical role of β2-microglobulin in cognitive disorders
Source：Xin Wang
2023-03-31
Down syndrome (DS), also known as trisomy 21, is the most common cause of congenital intellectual disability. Currently, the incidence of DS in newborns is close to 1/800, and it is estimated that there are approximately 1 million individuals with DS in China, placing a heavy burden on families and society. In addition to neurological dysfunction, people with DS also exhibit a high incidence of hematological disorders, such as leukemia and autoimmune diseases.
On March 2, 2023, Dr. Xin Wang's team from Xiamen University published a research article titled "β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function" in Cell, revealing the relationship between immune dysregulation and central nervous system pathology in DS and providing a new perspective for understanding the mechanisms of cognitive impairment in DS.
Wang et al. discovered that peripheral immunity plays a critical role in cognitive impairment in DS, revealing a new mechanism by which increased levels of β2-microglobulin (B2M) in the blood of individuals with DS can cross the blood-brain barrier and disrupt synaptic function. The team further found that reducing peripheral B2M levels through intravenous antibody injection markedly restored cognitive function in DS mice.
B2M is well-known for its key role in the immune system. As a component of major histocompatibility complex I (MHC-I), MHC-I/B2M presents antigenic peptides to T-cells. In addition, B2M can also fall from MHC-I and exists in its free form. In individuals with DS, the levels of free B2M are markedly upregulated, which can adversely affect the nervous system. In this study, Wang et al. discovered that the function of B2M in the nervous system is completely different from its classical role in the immune system. Specifically, B2M inhibits N-methyl-D-aspartate (NMDA) receptor function, which is crucial for learning and memory, leading to cognitive impairment.
The research team found that reducing B2M levels through gene knockout or antibody injection can markedly improve learning and memory in DS mouse models, suggesting that B2M may represent a new therapeutic target for treating cognitive impairment in DS. Although gene knockout can effectively restore cognitive function in DS mice, it is not clinically applicable as a treatment for DS. To seek more feasible treatment methods, the research team identified a short peptide that can inhibit the binding of B2M to NMDA receptors. Injecting this peptide into DS mice restored cognitive function without interfering with the normal immune function. Moreover, the research team found that this peptide can improve age-related cognitive impairment in aged mice, indicating that B2M may act as a common target for multiple cognitive disorders. This study reveals a new mechanism for cognitive dysfunction and provides a potential therapeutic strategy.
Article link：https://doi.org/10.1016/j.cell.2023.01.021
On March 2, 2023, Dr. Xin Wang's team from Xiamen University published a research article titled "β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function" in Cell, revealing the relationship between immune dysregulation and central nervous system pathology in DS and providing a new perspective for understanding the mechanisms of cognitive impairment in DS.
Wang et al. discovered that peripheral immunity plays a critical role in cognitive impairment in DS, revealing a new mechanism by which increased levels of β2-microglobulin (B2M) in the blood of individuals with DS can cross the blood-brain barrier and disrupt synaptic function. The team further found that reducing peripheral B2M levels through intravenous antibody injection markedly restored cognitive function in DS mice.
B2M is well-known for its key role in the immune system. As a component of major histocompatibility complex I (MHC-I), MHC-I/B2M presents antigenic peptides to T-cells. In addition, B2M can also fall from MHC-I and exists in its free form. In individuals with DS, the levels of free B2M are markedly upregulated, which can adversely affect the nervous system. In this study, Wang et al. discovered that the function of B2M in the nervous system is completely different from its classical role in the immune system. Specifically, B2M inhibits N-methyl-D-aspartate (NMDA) receptor function, which is crucial for learning and memory, leading to cognitive impairment.
The research team found that reducing B2M levels through gene knockout or antibody injection can markedly improve learning and memory in DS mouse models, suggesting that B2M may represent a new therapeutic target for treating cognitive impairment in DS. Although gene knockout can effectively restore cognitive function in DS mice, it is not clinically applicable as a treatment for DS. To seek more feasible treatment methods, the research team identified a short peptide that can inhibit the binding of B2M to NMDA receptors. Injecting this peptide into DS mice restored cognitive function without interfering with the normal immune function. Moreover, the research team found that this peptide can improve age-related cognitive impairment in aged mice, indicating that B2M may act as a common target for multiple cognitive disorders. This study reveals a new mechanism for cognitive dysfunction and provides a potential therapeutic strategy.
Article link：https://doi.org/10.1016/j.cell.2023.01.021
