Biology subjects

Venero, J. L.

Publications and source records attributed to Venero, J. L..

8 recordsLinked to original sources

bioRxiv2026

Galectin-3 drives tau-associated neuroinflammation, white matter degeneration and proteomic dysregulation

Tau pathology is a central driver of neurodegeneration, yet the molecular mechanisms linking tau accumulation to neuroinflammation, metabolic failure, and white matter degeneration remain incompletely understood. Galectin-3 (Gal3) is an inflammation-associated lectin expressed by activated microglia and has been implicated in neurodegenerative disease progression. Here, we investigated whether Gal3 modulates tau-driven pathology across cellular, molecular, and systems levels. Using the P301S tauopathy mouse model with genetic deletion of Gal3, we show that Gal3 loss robustly attenuates tau pathology across vulnerable brain regions, including cortex, hippocampus, and piriform-entorhinal cortex. Gal3 deletion reduced hyperphosphorylated and pathological tau species, normalized tau kinase signaling, and restored mitochondrial and vesicular trafficking pathways disrupted by tau accumulation. Proteomic and phosphoproteomic analyses revealed widespread normalization of tau-associated immune, metabolic, and trafficking pathways, with Tau-Gal3KO mice clustering closely with wild-type controls. In parallel, Gal3 deletion markedly reduced microglial activation and Gal3-positive inflammatory signatures, preserved white matter integrity, prevented axonal degeneration, and normalized oligodendrocyte and myelin abnormalities. Functionally, Gal3 deficiency enhanced microglial myelin phagocytosis and lysosomal degradation both in vitro and in vivo, suggesting improved clearance of myelin debris under inflammatory stress. Cell-type-specific analyses further revealed restoration of mitochondrial complex I subunit expression in both excitatory neurons and parvalbumin-positive interneurons. Importantly, translational studies in human iPSC-derived neurons demonstrated that extracellular Gal3 exacerbates tau hyperphosphorylation and aggregation following tau seeding, effects that were reversed by pharmacological Gal3 inhibition. Together, these findings identify Galectin-3 as a central upstream regulator linking tau pathology to neuroinflammation, proteomic dysregulation, mitochondrial dysfunction, and white matter degeneration. Targeting Gal3 represents a promising therapeutic strategy to mitigate tau-driven neurodegenerative processes.

neuroscience↗

bioRxiv2025

Metabolic and transcriptional adaptations to phagocytosis in microglia sustain their functionality and regenerative properties

Phagocytosis of apoptotic cells, or efferocytosis, is a tightly regulated process that ensures tissue homeostasis and prevents mounting inflammatory responses. In the brain parenchyma, it is executed by microglia, which are encumbered by large numbers of apoptotic debris generated during development, in adult neurogenic niches, aging, and brain diseases. Emerging evidence suggest that phagocytosis is not limited to garbage disposal, but triggers adaptations in the phagocytes that may have a functional impact. To test it we developed an in vivo model of superphagocytosis induced by low cranial irradiation (LCI, 2Gy) that specifically induced apoptosis in the neurogenic niche of the adult hippocampus, synchronizing microglia in a phagocytic state within 6h and leading to full clearance by 24h. Single cell RNA sequencing and metabolomics revealed an unexpected oxidative stress in post-phagocytic microglia, accompanied by catabolic shutdown, mitochondrial remodeling, increased expression of galectin 3, and production of polyamines that led to cell death and compensatory proliferation. To test whether these changes impaired subsequent microglial phagocytosis, we used a glioblastoma model treated with sequential irradiation to induce tumor cell apoptosis. The phagocytosis efficiency of tumor-associated microglia/macrophages was comparable in the first and second apoptotic challenge, suggesting that the metabolic remodeling induced by phagocytosis was adaptive and destined to sustain their functionality. Finally, we assessed the functional impact of post-phagocytosis adaptations using galectin 3 deficient mice under LCI. We found that the recovery of the neurogenic niche after LCI strongly depended on galectin 3, demonstrating the regenerative capacity of post-phagocytic microglia. Overall, our data unveils the complexity of post-phagocytosis adaptations in microglia, underscoring their unexplored therapeutic potential in brain disorders.

neuroscience↗

bioRxiv2025

Galectin-3 deletion modulates microglial phenotype and Aβ response via TREM2 activation while attenuating neuroinflammation

Neuroinflammation is a hallmark of Alzheimers disease (AD), yet the molecular mediators driving microglial dysfunction and neurotoxicity remain poorly understood. Here, we identify Galectin-3 (Gal3) as a central regulator of plaque-associated microglial responses, linking amyloid-beta (A{beta}) aggregation, lysosomal function and plaque-associated neuritic damage. Using postmortem brain tissue from AD patients, we demonstrated that Gal3 microglia are selectively enriched around highly immunogenic dense-core plaques, and correlate with increased LAMP1+ dystrophic neurites. Notably, Gal3 was also detected in extra-microglial dystrophic structures and in close association with extracellular amyloid fibrils, suggesting a role in both intracellular and extracellular A{beta} dynamics. In APP mice, Gal3 deficiency resulted in more compact plaques, reduced neuronal dystrophies and increased TREM2 expression around amyloid plaques, suggesting altered plaque-associated microglial responses. Mechanistically, in vitro studies revealed that Gal3 modulates A{beta} uptake and its intracellular processing while lysosomal stress conditions showed increased A{beta} fibrillation from monomeric species in Gal3-deficient microglia. In parallel, cell-free assays demonstrated that Gal3 directly interacts with A{beta} and selectively inhibits secondary nucleation, thereby stabilizing intermediate assemblies associated with increased neurotoxic potential. Finally, in silico and transcriptomic analysis revealed that Gal3 interacts with key immune receptor patterns, having leucine-rich repeats as well as immunoglobulin-like domains. Moreover, Gal3 favors pro-inflammatory microglial programs, while its deletion suppresses type I interferon and microglial neurodegenerative (MGnD) signatures. Together, these findings position Gal3 as a central regulator of amyloid aggregation, lysosomal dysfunction, and microglial activation, driving a neurotoxic phase of AD and highlighting a potential therapeutic window for intervention. Significance StatementNeuroinflammation and amyloid-beta (A{beta}) plaques drive Alzheimers disease progression, but the molecular bridges between plaque formation, microglial dysfunction, and neurodegeneration remain unclear. This study identifies Galectin-3 (Gal3) as a pivotal regulator at this interface. We demonstrate that Gal3 is enriched around amyloid dense-core plaques in human brains and directly shapes A{beta} aggregation into highly neurotoxic intermediate structures. Genetic deletion of Gal3 in Alzheimers mouse models reduces nerve cell damage and change microglial cells toward a protective, less inflammatory state. By linking extracellular protein aggregation with intracellular lysosomal stress and inflammatory gene expression, these findings establish Gal3 as a major driver of Alzheimers neurotoxicity and highlight it as a promising therapeutic target

neuroscience↗

bioRxiv2024

Drug screening targeting TREM2-TYROBP transmembrane binding

TREM2 encodes a microglial membrane receptor involved in the disease-associated microglia (DAM) phenotype whose activation requires the transmembrane interaction with TYROBP. Mutations in TREM2 represent a high-impact risk factor for Alzheimers disease (AD) which turned TREM2 into a significant drug target. We present a bacterial two-hybrid (B2H) system designed for high-throughput screening of modulators for the TREM2-TYROBP transmembrane interaction. In a pilot study, 315 FDA-approved drugs were analyzed to identify potential binding modifiers. Our pipeline includes multiple filtering steps to ensure candidate specificity. The screening suggested two potential candidates that were finally assayed in the human microglial cell line HMC3. Upon stimulation with anti-TREM2 mAb, pSYK/SYK ratios were calculated in the presence of the candidates. As a result, we found that varenicline, a smoking cessation medication, can be considered as a transmembrane agonist of the TREM2-TYROBP interaction.

molecular biology↗

bioRxiv2023

Galectin-3 depletion tames pro-tumoural microglia and restrains cancer cells growth

The glycoprotein Galectin-3 (Gal-3) is a multifunctional molecule that plays a pivotal role in the initiation and progression of various central nervous system diseases, including cancer. Although the involvement of Gal-3 in tumour progression, resistance to treatment and immunosuppression has long been studied in different cancer types, mainly outside the central nervous system, its elevated expression in myeloid and glial cells underscores its profound impact on the brains immune response. In this context, microglia and infiltrating macrophages, the predominant non-cancerous cells within the tumour microenvironment, assume critical roles in establishing an immunosuppressive milieu in diverse brain tumours. Through the utilisation of primary cell cultures and immortalised microglial cell lines, we have elucidated the central role of Gal-3 in promoting cancer cell migration, invasion, and an immunosuppressive microglial phenotypic activation. Furthermore, employing two distinct in vivo models encompassing primary (glioblastoma) and secondary brain tumours (breast cancer brain metastasis), our histological and transcriptomic analysis show that Gal-3 depletion triggers a robust pro-inflammatory response within the tumour microenvironment, notably based on interferon-related pathways. Interestingly, this response is prominently observed in tumour-associated microglia and macrophages (TAMs), resulting in the suppression of cancer cells growth.

neuroscience↗

bioRxiv2021

Arg1+ microglia are critical for shaping cognition in female mice

Diversity within microglia, the resident brain immune cells, is reported. Whether microglial subsets constitute different subtypes with intrinsic properties and unique functions has not been fully elucidated. Here, we describe a microglial subtype characterized by the expression of the enzyme Arginase-1, i.e. Arg1 +microglia, which is found predominantly in the cholinergic neuron-rich forebrain region during early postnatal development. Arg1+ microglia are frequently observed in close apposition to neurons and exhibit a distinctive molecular signature reflecting a reactive profile. Arg1 deficiency in microglia results in impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, and cognitive behavioural deficiencies in female mice. Our results expand on microglia diversity and provide insights into distinctive spatiotemporal functions exerted by microglial subtypes.

neuroscience↗

bioRxiv2019

TET2 regulates the neuroinflammatory response in microglia

Epigenetic mechanisms regulate distinct aspects of the inflammatory response in various immune cell types. Despite the central role for microglia, the resident macrophages of the brain, in neuroinflammation and neurodegeneration little is known about their epigenetic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-{kappa}B-dependent pathway. We found that TET2 regulates early gene transcriptional changes that lead to early metabolic alterations, as well as a later inflammatory response independently of its 5mC oxidation activity at the affected genes. We further show that TET2 regulates the proinflammatory response in microglia induced by intraperitoneal injection of LPS in vivo. We observed that microglia associated to amyloid {beta} plaques, recently defined as disease-associated microglia, expressed TET2 in brain tissue from individuals with Alzheimers disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response, and suggest TET2 as a potential target to combat neurodegenerative brain disorders.

neuroscience↗

bioRxiv2018

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

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.

neuroscience↗