Previous work by Mount Sinai researchers and others discovered that proteins that are enhanced in young blood, consisting of TIMP2, could be harnessed to revitalize brain function in aged animals by affecting plasticity– or the versatility of neural processes related to memory– in the hippocampus. In spite of that important discovery, little was understood about the biology of how TIMP2 controls plasticity of the hippocampus at the molecular level.
“TIMP2 manages these processes by changing the versatility of the microenvironment through components of the extracellular matrix. For their work, the group utilized a mutant mouse design mimicking the loss of TIMP2 levels in the blood and hippocampus that is known to occur with age. These designs, in combination with RNA sequencing, confocal imaging, super-resolution microscopy, and behavioral studies, enabled for an in-depth molecular evaluation of TIMP2s regulation of plasticity.
Comprehending Aging and Neurodegenerative Disorders
Aging is known to be the leading threat factor for lots of neurodegenerative conditions, including Alzheimers illness. Previous work by Mount Sinai researchers and others found that proteins that are enhanced in young blood, including TIMP2, might be harnessed to rejuvenate brain function in aged animals by affecting plasticity– or the versatility of neural procedures connected to memory– in the hippocampus. In spite of that essential discovery, little was learnt about the biology of how TIMP2 regulates plasticity of the hippocampus at the molecular level.
Accumulation of extracellular matrix content in brain of TIMP2-deficient “KO” mice (left column) that results in impaired plasticity procedures, consisting of the migration of adult-born nerve cells (right column). Credit: Mount Sinai Health System
Insights Into TIMP2s Molecular Mechanism
” In our latest study, we detailed a molecular link involving this protein that connects processes of plasticity, consisting of the generation of new neurons in the adult years, to the structural nature– or what we call the extracellular matrix– of the hippocampal microenvironment,” says Joseph Castellano, PhD, 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 changing the versatility of the microenvironment through parts of the extracellular matrix. Studying paths that control the extracellular matrix could be important for developing unique treatments for illness in which plasticity is affected.”
Ingenious Research Methods and Findings
For their work, the team utilized a mutant mouse model mimicking the loss of TIMP2 levels in the blood and hippocampus that is known to accompany age. The team likewise developed a design that enabled scientists to particularly erase the pool and target of TIMP2 revealed by neurons in the hippocampus. These designs, in mix with RNA sequencing, confocal imaging, super-resolution microscopy, and behavioral studies, permitted a comprehensive molecular assessment of TIMP2s policy of plasticity.
The scientists, including first author Ana Catarina Ferreira, PhD, a postdoctoral fellow in Dr. Castellanos group, found out that the loss of TIMP2 results in an accumulation of extracellular matrix elements in the hippocampus that happens alongside a decrease in plasticity processes, including the generation of adult-born neurons, synaptic stability, and memory. The extracellular matrix is a network of many macromolecular components that comprise the structural microenvironment around and between cells.
Implications and Future Research Directions
” We straight targeted this phenotype with an enzyme delivered to the hippocampus that impacts the extracellular matrix and found that plasticity processes normally impaired in the setting of decreased TIMP2 were now brought back,” keeps in mind Dr. Castellano. “This finding has essential ramifications for basically understanding how plasticity is regulated at the structural level in brain areas associated with memory.”
In general, the findings recommend that targeting processes that manage the extracellular matrix might be an important instructions for developing methods that improve plasticity in the brain. Dr. Castellano, whose lab is concentrated on defining factors with the possible to reverse functions of brain aging, prepares to explore molecules beyond TIMP2 that regulate the extracellular matrix, and is positive about where this research might take the field in the context of mitigating a range of conditions associated with aging.
Referral: “Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix intricacy” by Ana Catarina Ferreira, Brittany M. Hemmer, Sarah M. Philippi, Alejandro B. Grau-Perales, Jacob L. Rosenstadt, Hanxiao Liu, Jeffrey D. Zhu, Tatyana Kareva, Tim Ahfeldt, Merina Varghese, Patrick R. Hof and Joseph M. Castellano, 2 November 2023, Molecular Psychiatry.DOI: 10.1038/ s41380-023-02296-5.
The research study was supported by moneying from the National Institutes of Health, National Institute on Aging (R01AG061382, RF1AG072300, T32AG049688).
Scientists at Mount Sinai have discovered how the protein TIMP2 affects the hippocampus, a brain location essential for memory and knowing. Using advanced methods in mutant mouse models, the group showed that reducing TIMP2 levels resulted in decreased plasticity and memory function.
Scientists have revealed how the protein TIMP2 manages brain plasticity, particularly in the hippocampus, offering new insights into treating age-related disorders like Alzheimers by targeting the brains extracellular matrix.
Mount Sinai scientists have actually shed important light on the mechanism of an essential protein that controls the plasticity and function of the hippocampus, an essential brain region included in memory and knowing, and that reduces with age in mice.
The groups findings, published in Molecular Psychiatry, might pave the method for a better understanding of how the protein, called tissue inhibitor of metalloproteinases 2 (TIMP2), might potentially be targeted in age-related disorders like Alzheimers illness to assist bring back impacted molecular procedures in the brain.