Eduardo Ramirez Lopez

All Publications

• Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition. Immunity Navarro Negredo, P., You, J., Hauptschein, M., Schroer, A. B., Richard, D. J., Abhiraman, G. C., Tsai, A. P., Sun, E. D., Notarangelo, G., Ramirez-Matias, J., Zhou, O. Y., Buckley, M. T., Malacon, K. E., Xu, L., Sucharov, J., Ramirez Lopez, E., Picton, L., Wyss-Coray, T., Saxton, R. A., Fernandes, R. A., Villeda, S. A., Garcia, K. C., Brunet, A. 2026

  Abstract

  The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.

  View details for DOI 10.1016/j.immuni.2026.01.016

  View details for PubMedID 41619730

• Spatial and single-cell transcriptomics reveal the reorganization of cerebellar microglia with aging. Cell reports Tsai, A. P., Henze, D. E., Ramirez Lopez, E., Haberberger, J., Dong, C., Lu, N., Atkins, M., Costa, E. K., Farinas, A., Oh, H. S., Moran-Losada, P., Le Guen, Y., Isakova, A., Quake, S. R., Wyss-Coray, T. 2025; 44 (12): 116624

  Abstract

  The cerebellum, essential for motor coordination and increasingly recognized for its role in cognition, is typically considered more resilient to aging and largely spared from hallmark Alzheimer's disease (AD) pathology. However, transcriptomic analyses across fifteen mouse brain regions revealed that the cerebellum undergoes some of the earliest and most pronounced age-related changes. To investigate cerebellar aging, we applied single-nucleus RNA sequencing (RNA-seq), microglial bulk RNA-seq, and multiplexed error-robust fluorescence in situ hybridization (MERFISH)-based spatial transcriptomics. Microglia showed the most prominent changes, including elevated expression of a neuroprotective signature and reduced expression of a lipid-droplet-accumulating signature compared to hippocampal microglia. Spatial analyses further revealed that aged cerebellar microglia were positioned in close proximity to granule cells. Utilizing this relationship, we identified a proximity-dependent transcriptional state defined by the neuron-associated microglial signature. This signature reveals a region-specific microglial adaptation, highlighting cerebellar reorganization with age and potential resilience to AD.

  View details for DOI 10.1016/j.celrep.2025.116624

  View details for PubMedID 41307999

• Color-neutral and reversible tissue transparency enables longitudinal deep-tissue imaging in live mice. bioRxiv : the preprint server for biology Keck, C. H., Schmidt, E. L., Roth, R. H., Floyd, B. M., Tsai, A. P., Garcia, H. B., Cui, M., Chen, X., Wang, C., Park, A., Zhao, S., Liao, P. A., Casey, K. M., Reineking, W., Cai, S., Zhang, L., Yang, Q., Yuan, L., Baghdasaryan, A., Lopez, E. R., Cooper, L., Cui, H., Esquivel, D., Brinson, K., Chen, X., Wyss-Coray, T., Coleman, T. P., Brongersma, M. L., Bertozzi, C. R., Wang, G. X., Ding, J. B., Hong, G. 2025

  Abstract

  Light scattering in biological tissue presents a significant challenge for deep in vivo imaging. Our previous work demonstrated the ability to achieve optical transparency in live mice using intensely absorbing dye molecules, which created transparency in the red spectrum while blocking shorter-wavelength photons. In this paper, we extend this capability to achieve optical transparency across the entire visible spectrum by employing molecules with strong absorption in the ultraviolet spectrum and sharp absorption edges that rapidly decline upon entering the visible spectrum. This new color-neutral and reversible tissue transparency method enables optical transparency for imaging commonly used fluorophores in the green and yellow spectra. Notably, this approach facilitates tissue transparency for structural and functional imaging of the live mouse brain labeled with yellow fluorescent protein and GCaMP through the scalp and skull. We show that this method enables longitudinal imaging of the same brain regions in awake mice over multiple days during development. Histological analyses of the skin and systemic toxicology studies indicate minimal acute or chronic damage to the skin or body using this approach. This color-neutral and reversible tissue transparency technique opens new opportunities for noninvasive deep-tissue optical imaging, enabling long-term visualization of cellular structures and dynamic activity with high spatiotemporal resolution and chronic tracking capabilities.

  View details for DOI 10.1101/2025.02.20.639185

  View details for PubMedID 40060493