Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

Boza Serrano, A.; Ruiz, R.; Sanchez Varo, R.; Yang, Y.; Garcia-Revilla, J.; Paulus, A.; Jimenez Ferrer, I.; The Netherland Brain,; Wennstrom, M.; Vilalta, A.; Dunning, C.; Davila, J. C.; Allendorf, D.; Swanberg, M.; Stegmayr, J.; Jimenez, S.; Roca-Ceballos, M. A.; Navarro-Garrido, V.; L. Hsieh, C.; Miguel-Real, L.; Englund, E.; Linse, S.; Leffler, H.; J. Nilsson, U.; Gutierrez, A.; Brown, G. C.; Vitorica, J.; Venero, J. L.; Deierborg, T.

doi:10.1101/477927

Home/Archive/bioRxiv

bioRxiv · 10.1101/477927

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

View original source ↗Export metadata ↓

Abstract

Alzheimers disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (A{beta}) peptide, intraneuronal tau neurofibrillary tangles and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimers disease) mice, and found specifically expressed in microglia associated with A{beta} plaques. Single nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated to an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data demonstrated the requirement of gal3 to fully activate microglia in response to fibrillar A{beta}. Gal3 deletion decreased the A{beta} burden in 5xFAD mice and improved cognitive behavior. Electron microscopy of gal3 in AD mice demonstrated i) a preferential expression of gal3 by plaque-associated microglia, ii) its presence in the extracellular space and iii) its association to A{beta} plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure A{beta}. Importantly, a single intrahippocampal injection of gal3 along with A{beta} monomers in WT mice was sufficient to induce the formation of insoluble A{beta} aggregates that were absent when gal3 was lacking. High-resolution microscopy (STORM) demonstrated close co-localization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 CRD domain. Furthermore, gal3 stimulated the TREM2-DAP12 signaling pathway. In conclusion, we provide evidence that gal3 is a central regulator of microglial immune response in AD. It drives proinflammatory activation and A{beta} aggregation, as well as acting as an endogenous ligand to TREM2, a key receptor driving microglial response under disease conditions. Gal3 inhibition may, hence, be a potential pharmacological approach to counteract AD.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Boza Serrano, A., Ruiz, R., Sanchez Varo, R., Yang, Y., Garcia-Revilla, J., Paulus, A., Jimenez Ferrer, I., The Netherland Brain,, Wennstrom, M., Vilalta, A., Dunning, C., Davila, J. C., Allendorf, D., Swanberg, M., Stegmayr, J., Jimenez, S., Roca-Ceballos, M. A., Navarro-Garrido, V., L. Hsieh, C., Miguel-Real, L., Englund, E., Linse, S., Leffler, H., J. Nilsson, U., Gutierrez, A., Brown, G. C., Vitorica, J., Venero, J. L., Deierborg, T.. 2018-12-04. Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease. https://doi.org/10.1101/477927

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Next generation Human Neocortical Neurosolver model with biophysically realistic somatic, dendritic and synaptic dynamics

The Human Neocortical Neurosolver (HNN) is an open-source biophysical modeling tool for multiscale interpretation of human electroencephalography (EEG) and magnetoencephalography (MEG) signals. HNN's foundation is a pre-tuned canonical neocortical circuit model consisting of excitatory pyramidal neurons and inhibitory interneurons in supra- (L2/3) and infragranular (L5) layers. This model was originally developed based on studies in rodent and non-human primate cortices when dynamics of human neurons were poorly characterized. Yet recent advances in recordings from human tissue now provide unprecedented detail to update the model. Here, we present a significantly updated model for use in the HNN software, with electrophysiological properties and synaptic connections tuned to human tissue. Beyond reproducing biologically realistic somatic dynamics, the pyramidal cells simulate dendritic calcium (Ca2+) spikes in the L5 extratelencephalic-projecting (ET) neurons, and shorter dendritic spikes in the L2/3 pyramidal neurons. We demonstrate how the updated circuitry and new features in the HNN software can be used to disentangle somatic, synaptic, and dendritic contributions to human E-/MEG signatures. The model is distributed with workflows to simulate event-related responses and oscillations, and tutorials demonstrating how membrane potentials, Ca2+ dynamics, and synaptic currents can be recorded and visualized. These enhancements allow extensive model validations based on in vitro and in vivo electrophysiology, voltage and Ca2+ imaging, and provide users with novel insights on the mechanisms underlying E-/MEG signals.

neuroscience↗

bioRxiv2026

A biological light sheet links cellular voltage to mesoscopic brain dynamics

Membrane voltage is the fundamental currency of neural computation, yet cellular-resolution voltage imaging of large neuronal populations in vivo remains limited by trade-offs among imaging speed, field of view, and optical sectioning. We overcome this challenge by encoding a biological light sheet in the brain: Selective Plane Expression (SPress) restricts fluorescent indicator expression to a user-defined, 20-m-thick plane, suppressing background at its source. Following one-time two-photon photoactivation, SPress enables standard widefield microscopes to capture high-contrast kilohertz voltage dynamics from hundreds of densely labeled neurons across millimeter-scale cortical sheets and columns in vivo. These recordings reveal mesoscopic subthreshold waves that flexibly reorganize population-wide spike timing, together with cellularscale wavefront microstructure that preserves stereotyped local recruitment biases. By shifting optical sectioning from instrumentation to gene expression, SPress makes kilohertz cellular resolution voltage imaging accessible across mesoscopic scales.

neuroscience↗

bioRxiv2026

Persistent hippocampal traces of lifelong spatial memory

Memory presents a biological paradox: the brain changes continuously, yet a brief experience can influence behavior for a lifetime. How such memories are stored in brain circuits remains unclear. Here we show that two days in a binary-tree maze leave mice with spatial memories that survive repeated 90-day absences over as much as a year. Across return visits, mice explored the maze more efficiently than when naive and resumed direct runs to a reward location sooner, both by a factor of 3. Chronic calcium imaging of the same hippocampal CA1 neurons showed that although most neurons had changed their preferred locations, the population activity at a given maze location still resembled the pattern from 90 days earlier. Furthermore, even when a neuron's place fields changed location, they tended to remain at the same branching level of the binary tree, reflecting the local geometry of the maze. In return sessions where the neural tuning for branching level was preserved more accurately, the mouse explored the environment more efficiently. Population patterns were best preserved near the reward location, and more reliable neural activity there accompanied earlier direct runs to the reward. With repeated experience, spatial representations changed less, both within a visit and across the long absences. A brief experience thus left selective hippocampal traces that survived months of absence despite drift, grew more durable with each return, and were correlated with memory in navigation behavior.

neuroscience↗