Researchers at Mount Sinai have discovered how the TMP2 protein affects the hippocampus, an area of the brain important for memory and learning. Using advanced techniques in mutant mouse models, the team showed that reducing TIMP2 levels led to reduced plasticity and memory loss.
Researchers have revealed how the protein TIMP2 regulates brain plasticity, particularly in the hippocampus, providing new insights into the treatment of age-related diseases. Alzheimer’s By targeting the brain’s extracellular matrix.
Mount Sinai scientists have shed important light on a key protein mechanism that regulates the plasticity and function of the hippocampus, which is involved in memory and learning and declines with age in mice.
The team’s findings, published in Molecular psychiatryA protein known as the tissue inhibitor of metalloproteinase 2 may pave the way for a better understanding of how it fights age-related disorders such as Alzheimer’s disease by restoring damaged molecular processes in the brain.
Understanding aging and neurodegenerative disorders
Aging is known to be a high risk factor for many neurodegenerative disorders, including Alzheimer’s disease. Previous work by the Mount Sinai researchers and others has shown that proteins enriched in the blood of young adults, including TIMP2, can be used to restore brain function by influencing plasticity – or the flexibility of neural processes associated with memory – in the hippocampus. Despite that important finding, little was known about the biology of how TMP2 regulates hippocampal plasticity at the molecular level.
Accumulation of extracellular matrix content in TMP2-deficient “KO” mice (left column) leads to impaired plastic processes, including migration of adult-born neurons (right column). Credit: Mount Sinai Health System
Insights into the molecular mechanism of TIMP2
“In our recent study, we have identified a molecular link involving this protein that links plastic processes, including the formation of new neurons during adulthood, to the structural nature — or extracellular matrix — of the hippocampal microenvironment,” Joseph said. Castellano, PhD, assistant professor of neuroscience and neurology at the Icahn School of Medicine at Mount Sinai and senior author. “TIMP2 regulates these processes by altering the dynamics of the microenvironment through extracellular matrix components. Studying the pathways that regulate the extracellular matrix may be useful for designing new treatments for diseases in which plasticity is impaired.”
Creative research methods and discoveries
For their work, the team used a mutant mouse model that mimics the age-related loss of TIMP2 levels in the blood and hippocampus. The team also developed a model that allowed researchers to specifically target and delete the pool of TIMP2 expressed by neurons in the hippocampus. These models, in combination with RNA Sequencing, confocal imaging, high-resolution microscopy, and behavioral studies allowed for detailed molecular investigation of the regulation of TIMP2 plasticity.
The researchers, lead author Ana Catarina Ferreira, PhD, a postdoctoral fellow in Dr. Castellano’s group, found that loss of TMP2 causes accumulation of extracellular matrix components in the hippocampus, which is associated with reduced plasticity processes, including generation. In adult-born neurons, synaptic integrity and memory. The extracellular matrix is a network of several macromolecular components that comprise the structural microenvironment between cells and cells.
Implications and future research directions
“We directly targeted this phenotype with an enzyme delivered to the hippocampus that affects the extracellular matrix and found that normal plasticity processes were restored in the presence of reduced TIMP2,” said Dr. Castellano. “This finding has important implications for fundamentally understanding how plasticity is modulated at the structural level of brain regions involved in memory.”
Overall, the findings suggest that targeting processes that regulate the extracellular matrix may be an important direction for designing approaches that improve plasticity in the brain. Dr. Castellano’s labs are focused on identifying factors that have the potential to alter the aging process of the brain, and beyond TMP2, they plan to investigate molecules that regulate cell matrix regulation, and hope that this research can lead to a reduction. Various diseases related to aging.
Reference: “Neuronal TMP2 Regulates Hippocampus-Based Plasticity and Extracellular Matrix Complexity” By Ana Catarina Ferreira, Brittany M. Hemmer, Sarah M. Philippi, Alejandro B. Grau-Perells, Jacob L. Rosenstadt, Hanxiao Liu, Jeffrey D. Zhu, Tatiana Kareva, Tim Ahfelt, Marina Varghese, Patrick R. Hoff and Joseph M. Castellano, 2 Nov 2023; Molecular psychiatry.
DOI: 10.1038/s41380-023-02296-5
The study was funded by National Institutes of HealthNational Institute on Aging (R01AG061382, RF1AG072300, T32AG049688).