Researchers at Mount Sinai have discovered how the protein TIMP2 affects the hippocampus, a brain area vital for memory and learning. In their latest study, the team showed that decreasing TIMP2 levels led to reduced plasticity and memory function. Insights gained from the study, published in Molecular Psychiatry, could offer new approaches to treating age-related disorders like Alzheimer’s disease by targeting the brain’s extracellular matrix.
Aging is the leading risk factor for several neurodegenerative disorders, including Alzheimer’s disease. Previous research had indicated that proteins enriched in young blood, such as TIMP2, could be used to rejuvenate brain function in aged animals by influencing the plasticity of the hippocampus. However, the molecular mechanism by which TIMP2 regulates hippocampal plasticity was not fully understood until now.
The team at Mount Sinai used a mutant mouse model to mimic the loss of TIMP2 levels in the blood and hippocampus that occurs with age. Additionally, they created a model to delete the pool of TIMP2 expressed by neurons in the hippocampus. Through advanced techniques like RNA sequencing, confocal imaging, super-resolution microscopy, and behavioral studies, the researchers were able to gain detailed insights into how TIMP2 regulates brain plasticity.
Lead author of the study, Joseph Castellano, PhD, Assistant Professor of Neuroscience and Neurology at the Icahn School of Medicine at Mount Sinai, explained that the research detailed a molecular link involving TIMP2, tying processes of plasticity, such as the generation of new neurons in adulthood, to the structural nature of the hippocampal microenvironment. He emphasized that this understanding of TIMP2’s role in regulating the extracellular matrix could be crucial for designing novel therapies for diseases that affect plasticity.
Perhaps most importantly, the study showed that targeting the extracellular matrix using an enzyme delivered to the hippocampus restored plasticity processes that had been impaired in the setting of reduced TIMP2 levels. This finding, according to Dr. Castellano, has important implications for understanding how plasticity is regulated at the structural level in brain regions involved in memory.
The study, supported by funding from the National Institutes of Health, National Institute on Aging, could open up new avenues for research into molecules beyond TIMP2 that regulate the extracellular matrix. The researchers at Mount Sinai are optimistic about where this research may lead the field in the context of mitigating a variety of disorders associated with aging.