Strengthening a weak link
The identification of a rare gene variant that increases the risk for Alzheimer’s disease has led researchers to explore a new approach to the treatment of neurodegenerative diseases.
The gene TREM2 plays an important role in the pathogenesis of a series of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, frontotemporal dementia (FTD) and Nasu-Hakola disease. Recent work has shown that a rare mutation in the gene is associated with an increased risk for Alzheimer’s. A team of researchers led by Christian Haass, who holds the Chair of Metabolic Biochemistry at LMU and is the designated spokesperson for the German Center for Neurodegenerative Diseases (DZNE) in Munich, has now ascertained how the mutation impairs the protein’s function.
Alzheimer’s disease, like many other neurodegenerative conditions, is characterized by the accumulation in parts of the brain of insoluble deposits (‘plaques’) made up of specific proteins and protein fragments. In the central nervous system, such deposits are normally disposed of by immune surveillance cells called microglia, which are functionally analogous to the phagocytic cells that engulf and degrade bacterial pathogens and denatured proteins in other tissues. However, as the brain gets older, the microglial cells gradually lose the ability to recognize and destroy these deposits, and may actually produce agents that facilitate their formation.
The TREM2 gene is activated specifically in the microglia, and is essential for their capacity to eliminate the extracellular plaques found in the aging brain. Its protein product is expressed on the cell surface and acts as a sensor, which recognizes and binds to dying cells, cell debris and lipids that are associated with the toxic protein deposits. Subsequently, the extracellular portion of TREM2 is enzymatically released into the medium, while the rest of the protein is degraded.
Haass and his colleagues have now shown that TREM2 is cleaved between amino acids 157 and 158. Remarkably, the recently mapped risk mutation replaces the histidine normally found at position 157 by the amino acid tyrosine, and the LMU team went on to show that this change alters the stability of TREM2, causing it to be cleaved more rapidly than the normal wild-type protein. Thus, unlike other TREM2 mutations, which result in the destruction of the protein before it reaches the cell surface, the newly identified variant is correctly transported to and inserted into the plasma membrane of the microglia. However, because it is abnormally sensitive to enzymatic cleavage, it is rapidly inactivated. “This suggests that stabilizing TREM2, by making it less susceptible to cleavage, might offer a viable therapeutic strategy,” says Haass. Indeed, the LMU team has already begun to generate antibodies designed to mask the cleavage site with a view to by increasing the amount of protein present on the microglial surface. A patent application was submitted a year ago, and negotiations with an American biotech company are underway.
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