OSCR

Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice.

Overview

Authors: Brittany M. Hemmer1,2,3,4,5, Sarah M. Philippi1,2,3,4,5, Ana Catarina Ferreira1,2,3,4, Samuele F. Petridis1,2,3,4, Annie Phan1,2,3,4, Joseph M. Castellano1,2,3,4
ORCID iDs: Brittany M. Hemmer, Sarah M. Philippi, Ana Catarina Ferreira, Samuele F. Petridis, Joseph M. Castellano
  1. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai,New York, NY USA
  2. Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai,New York, NY USA
  3. Department of Neurology, Icahn School of Medicine at Mount Sinai,New York, NY USA
  4. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai,New York, NY USA
  5. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai,New York, NY USA
Institutions: Icahn School of Medicine at Mount Sinai (United States)
Journal: Nature communications, volume 17, issue 1, article 8173
Dates: received 27 May 2025; accepted 4 June 2026; published online 12 August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-74906-z · PMID 42586968 · PMCID PMC13469711 · OpenAlex W7202299320
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, fMRI & imaging
Keywords: Neural ageing, Glial biology, Neuroimmunology, Cellular neuroscience, Neuro-vascular interactions
MeSH: Aging*, Microglia*, Tissue Inhibitor of Metalloproteinase-2*, Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Brain, CD68 Molecule, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis (* major topic)
Topic: Neuroinflammation and Neurodegeneration Mechanisms (Neurology, Neuroscience), according to OpenAlex
Funding: National Institute on Aging (R01AG061382, RF1AG072300, T32AG049688, R01AG061382-02S1)
Citations: cited by 1 paper (Europe PMC); 108 references in the paper

Abstract

There is little understanding of how aging serves as the strongest risk factor for several neurodegenerative diseases. Microglia undergo age-related maladaptive changes, including increased inflammation, impaired debris clearance, and cellular senescence, yet specific mediators that regulate these processes remain unclear. The aged brain is rejuvenated by youth-associated plasma factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown acts on the extracellular matrix (ECM) to regulate synaptic plasticity. Given emerging roles for microglia in these processes, we examined the impact of TIMP2 on microglial function. We show that TIMP2 deletion in mice exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, changes in lysosomal-associated markers and phagocytosis, and elevated levels of stress and inflammatory proteins in the brain extracellular space measured by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increases microglial CD68 and alters myelin phagocytosis. Treating aged mice with TIMP2 reverses several phenotypes observed in our deletion models, resulting in decreased microglial activation, reduced proportions of proinflammatory microglia, and enhanced phagocytosis of physiological substrates. Our results identify TIMP2 as a modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

snRNAseq and bulk RNAseq data generated in this study has been deposited to the NCBI’s Gene Expression Omnibus database and are available through accession numbers GSE297916 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE297916) and GSE297917 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE297917), respectively. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 5 keywords, 13 MeSH terms, 1 funder, 108 references.

Cite

This paper

Hemmer, B. M., Philippi, S. M., Ferreira, A. C., Petridis, S. F., Phan, A., & Castellano, J. M. (2026). Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice. Nature communications, 17(1), 8173. https://doi.org/10.1038/s41467-026-74906-z

BibTeX

@article{hemmer2026youth,
author = {Hemmer, Brittany M. and Philippi, Sarah M. and Ferreira, Ana Catarina and Petridis, Samuele F. and Phan, Annie and Castellano, Joseph M.},
title = {{Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice}},
journal = {Nature communications},
year = {2026},
month = aug,
volume = {17},
number = {1},
pages = {8173},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-74906-z},
url = {https://doi.org/10.1038/s41467-026-74906-z},
pmid = {42586968},
pmcid = {PMC13469711}
}

RIS

TY - JOUR
AU - Hemmer, Brittany M.
AU - Philippi, Sarah M.
AU - Ferreira, Ana Catarina
AU - Petridis, Samuele F.
AU - Phan, Annie
AU - Castellano, Joseph M.
TI - Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/08/12
VL - 17
IS - 1
SP - 8173
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-74906-z
UR - https://doi.org/10.1038/s41467-026-74906-z
LA - en
ER -

CSL-JSON

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