This Protein Could Be the Key to Turning Back Your Brain’s Aging Clock

This Protein Holds the Potential to Reverse Brain Aging

Researchers at Mount Sinai have made a significant breakthrough in understanding the role of the protein TIMP2 in brain aging. Specifically, they have uncovered how TIMP2 influences the hippocampus, a critical brain region responsible for memory and learning. Employing advanced techniques with mutant mouse models, the research team has demonstrated that a reduction in TIMP2 levels results in diminished plasticity and memory function.

TIMP2, short for tissue inhibitor of metalloproteinases 2, has emerged as a key player in regulating brain plasticity, especially within the hippocampus. This discovery offers fresh insights into addressing age-related neurological disorders, such as Alzheimer’s, by targeting the extracellular matrix within the brain.

Mount Sinai scientists have illuminated the intricate mechanisms through which TIMP2 governs hippocampal plasticity and function, which tend to decline with age in mice. Their findings, published in the journal Molecular Psychiatry, open the door to a deeper comprehension of how TIMP2 could potentially be targeted to restore disrupted molecular processes in the aging brain.

Aging and Neurodegenerative Disorders

Aging is recognized as the foremost risk factor for numerous neurodegenerative conditions, Alzheimer’s being a prime example. Prior research had already hinted at the potential of proteins found in youthful blood, including TIMP2, to rejuvenate brain function in older animals by impacting hippocampal plasticity—the brain’s ability to adapt and form memories. However, the molecular intricacies of how TIMP2 regulates hippocampal plasticity remained largely unknown.

Insights into TIMP2’s Molecular Mechanism

“In our latest study, we’ve elucidated a molecular connection involving TIMP2 that links plasticity processes, including the generation of new neurons in adulthood, to the structural characteristics, or what we refer to as the extracellular matrix, of the hippocampal microenvironment,” explained Joseph Castellano, PhD, Assistant Professor of Neuroscience and Neurology at the Icahn School of Medicine at Mount Sinai, and senior author of the research paper. “TIMP2 controls these processes by altering the flexibility of the microenvironment through components of the extracellular matrix. Investigating pathways that regulate the extracellular matrix could hold significance in devising novel therapies for conditions where plasticity is compromised.”

Innovative Research Methods and Findings

To conduct their research, the team utilized a mutant mouse model that mimicked the decline of TIMP2 levels in the bloodstream and hippocampus, a natural occurrence with aging. Additionally, they created a model that allowed them to specifically target and eliminate the pool of TIMP2 produced by hippocampal neurons. These models, in conjunction with RNA sequencing, confocal imaging, super-resolution microscopy, and behavioral studies, enabled a meticulous examination of how TIMP2 regulates plasticity at the molecular level.

The researchers, led by first author Ana Catarina Ferreira, PhD, a postdoctoral fellow in Dr. Castellano’s group, discovered that the reduction of TIMP2 leads to an accumulation of extracellular matrix components in the hippocampus. This accumulation coincides with a decrease in plasticity processes, including the generation of adult-born neurons, synaptic integrity, and memory. The extracellular matrix comprises a complex network of macromolecular components that form the structural microenvironment surrounding and connecting brain 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 plasticity processes typically impaired in the absence of sufficient TIMP2 were restored,” Dr. Castellano noted. “This discovery has significant implications for our fundamental understanding of how plasticity is regulated at the structural level in brain regions crucial for memory.”

Overall, these findings suggest that focusing on processes that regulate the extracellular matrix may represent a crucial avenue for designing interventions that enhance brain plasticity. Dr. Castellano, whose lab is dedicated to characterizing factors with the potential to counteract brain aging, intends to explore other molecules beyond TIMP2 that also influence the extracellular matrix. The outlook is promising for advancing research in the context of mitigating various disorders associated with the aging process.

Reference: “Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity” 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, published on November 2, 2023, in Molecular Psychiatry.
DOI: 10.1038/s41380-023-02296-5

The study received funding support from the National Institutes of Health, National Institute on Aging (R01AG061382, RF1AG072300, T32AG049688).

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• Molecular Psychiatry Article
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• National Institute on Aging