Mount Sinai researchers have discovered how the protein TIMP2 affects the hippocampus, a brain region essential for memory and learning. Using advanced techniques in mutant mouse models, the research team showed that reduced TIMP2 levels lead to decreased plasticity and memory function.
Researchers have uncovered how the protein TIMP2 regulates brain plasticity, particularly in the hippocampus, providing new insights into the treatment of age-related diseases such as: Alzheimer’s disease By targeting the brain’s extracellular matrix.
Mount Sinai scientists have shed valuable light on the mechanisms of a key protein that regulates plasticity and function in the hippocampus, a key brain region involved in memory and learning, and that decreases as mice age.
The team’s findings are molecular psychiatryThis protein, known as tissue inhibitor of metalloproteinase 2 (TIMP2), is a target in age-related diseases such as Alzheimer’s disease and has been shown to have the potential to help restore affected molecular processes in the brain. It could pave the way for better understanding.
Understanding aging and neurodegenerative diseases
Aging is known to be the greatest risk factor for many neurodegenerative diseases, including Alzheimer’s disease. Previous work by researchers at Mount Sinai has used proteins abundant in young blood, including TIMP2, to influence hippocampal plasticity, the flexibility of neural processes associated with memory. , it turns out that it may be possible to rejuvenate brain function in older animals. Despite this important discovery, little was known about the biology of how TIMP2 regulates hippocampal plasticity at the molecular level.
Accumulation of extracellular matrix content in the brains of TIMP2-deficient “KO” mice (left column) causes impairment of plasticity processes such as migration of adult-born neurons (right column). Credit: Mount Sinai Health System
Insights into the molecular mechanism of TIMP2
“Our latest research shows that molecules involved in this protein link processes of plasticity, including the generation of new neurons in adulthood, with the structural properties of the hippocampal microenvironment, or what we call the extracellular matrix. I explained the connections in detail,” Joseph said. Dr. Castellano is an assistant professor of neuroscience and neurology at the Icahn School of Medicine at Mount Sinai and senior author of the paper. “TIMP2 controls these processes by altering the plasticity of the microenvironment through components of the extracellular matrix. Studying the pathways that regulate the extracellular matrix could provide new treatments for diseases in which plasticity is affected. That could be important in designing the law.”
Innovative research methods and discoveries
The research team used a mutant mouse model that mimics the decline in TIMP2 levels in the blood and hippocampus that is known to occur with age. The researchers also created a model in which they could specifically target and delete a pool of TIMP2 expressed by neurons in the hippocampus. When combined with these models, RNA Sequencing, confocal imaging, super-resolution microscopy, and behavioral studies have enabled detailed molecular examination of TIMP2’s regulation of plasticity.
The researchers, including lead author Ana Catarina Ferreira, Ph.D., a postdoctoral fellow in Dr. Castellano’s group, found that TIMP2 deletion leads to the accumulation of extracellular matrix components in the hippocampus, which in turn contributes to plasticity processes including hippocampal generation. We learned that this occurs in parallel with the decline in Adult-born neurons, synaptic integrity, and memory. The extracellular matrix is a network of many macromolecular components that constitute the structural microenvironment around and between cells.
Implications and future research directions
“When we directly targeted this phenotype using enzymes delivered to the hippocampus that affect the extracellular matrix, we found that plasticity processes that are normally impaired in environments with reduced TIMP2 are restored,” Castellano says Dr. “This finding has important implications for our fundamental understanding of how plasticity is controlled at the structural level in brain regions involved in memory.”
Overall, this finding suggests that targeting processes that regulate the extracellular matrix may be an important direction for designing approaches to improve brain plasticity. Dr. Castellano’s lab is focused on characterizing factors that may reverse the hallmarks of brain aging, and plans to explore molecules other than TIMP2 that regulate the extracellular matrix, and this research will We are optimistic about the potential applications in the context of mitigating aging. Various disorders associated with aging.
Reference: “Neuronal TIMP2 controls hippocampus-dependent plasticity and extracellular matrix complexity” Ana Catarina Ferreira, Brittany M. Hemmer, Sarah M. Philippi, Alejandro B. Grau-Perales, Jacob L. Rosenstadt , Hanxiao Liu, Jeffrey D. Zhu, Tatiana Kaleva, Tim Erfeldt, Melina Varghese, Patrick R. Hoff, Joseph M. Castellano, November 2, 2023. molecular psychiatry.
DOI: 10.1038/s41380-023-02296-5
This research was supported by funding from. National Institutes of HealthNational Institute on Aging (R01AG061382, RF1AG072300, T32AG049688).
