Biology subjects

Sanz-Ros, J.

Publications and source records attributed to Sanz-Ros, J..

4 recordsLinked to original sources

bioRxiv2026

Therapeutic targeting of fibrin-microglia interactions ameliorates Alzheimer disease-related hyperexcitability and brain network dysfunction

Brain network dysfunction--including hyperexcitability, altered oscillations, and sleep disruption--is prominent in Alzheimers disease (AD), but the contribution of vascular-neuroimmune processes to these alterations remains unclear. Here, we blocked the pro-inflammatory interaction of the blood protein fibrin with microglia using genetic (Fgg{gamma}390-396A mice) and antibody-based (5B8 and THN392) strategies to test its role in AD-related network dysfunction. The 5xFAD model of AD exhibited network hyperexcitability associated with oscillatory slowing, sleep states, and disrupted sleep-circadian rhythms. These deficits were largely attenuated by blocking fibrin-microglia interactions in 5xFAD;Fgg{gamma}390-396A mice. Notably, pharmacological interventions after disease onset with both anti-fibrin antibodies similarly attenuated these AD-related network deficits and behavioral abnormalities. We conclude that vascular-neuroimmune processes driven by fibrin-microglia interactions promote AD-related network dysfunction and that targeting the fibrin-microglia axis--currently under clinical evaluation with the humanized antibody THN391-- represents a promising therapeutic strategy for AD. There is a companion manuscript submitted to bioRxiv (Yan et al., 2026).110 HIGHLIGHTSO_LIFibrin promotes AD-related network hyperexcitability and oscillatory slowing in 5xFAD mice C_LIO_LIFibrin promotes AD-related disruption of sleep and circadian rhythms in 5xFAD mice C_LIO_LIGenetic blocking of fibrin-microglia interactions rescues AD-related brain network dysfunction C_LIO_LIAnti-fibrin antibodies (5B8 and THN392) show acute and chronic therapeutic benefit C_LI

neuroscience↗

bioRxiv2024

Molecular Signatures of Resilience to Alzheimer's Disease in Neocortical Layer 4 Neurons

Single-cell omics is advancing our understanding of selective neuronal vulnerability in Alzheimers disease (AD), revealing specific subtypes that are either susceptible or resilient to neurodegeneration. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex and precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing RORB, CUX2, and EYA4. Layer 4 neurons in association neocortex also remained relatively preserved as AD progressed and shared overlapping molecular signatures of resilience. Early in the disease, resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotective factors, including GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1, and CSMD1. We also identified KCNIP4, which encodes a voltage-gated potassium (Kv) channel-interacting protein that interacts with Kv4.2 channels and presenilins, as a key factor linked to resilience. KCNIP4 was consistently upregulated in the early stages of pathology. Furthermore, AAV-mediated overexpression of Kcnip4 in a humanized AD mouse model reduced the expression of the activity-dependent genes Arc and c-Fos, suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a valuable resource for investigating mechanisms underlying resilience to neurodegeneration.

neuroscience↗

bioRxiv2024

Small extracellular vesicles from young adipose-derived stem cells ameliorate age-related changes in the heart of old mice.

BackgroundAging is a process characterized by a progressive decline in physiological functions. This decline contributes to an increased risk of various age-related diseases, including conditions such as heart failure or aortic stenosis. Recent advances have highlighted the potential of stem cell therapies in mitigating the adverse effects of aging. The mechanisms underlying the therapeutic effects of these cells appear to be largely paracrine, including the exchange of different molecules via extracellular vesicles (EVs). This work aims to investigate the potential of sEVs derived from young adipose-derived stem cells (ADSC-sEVs) in restoring structural, molecular, and functional changes associated with aging in the heart. MethodsAged C57BL/6J mice were treated intravenously with ADSC-sEVs from young mice or PBS as controls, young mice were also included to identify specific changes associated with aging. The impact of sEV treatment on cardiac function was assessed using transthoracic echocardiography and physical endurance tests. Histological and molecular analyses were conducted on heart tissue to evaluate structural changes and markers of senescence, inflammation, and oxidative stress. Additionally, a comprehensive metabolomic analysis was performed on heart tissues to identify changes in metabolic profiles associated with aging and treatment status. ResultsAdministration of ADSC-sEVs significantly improves several aging-associated cardiac parameters, including reductions in oxidative stress, inflammation, and cellular senescence. We also report on age-related changes reversal in myocardial structure and function, highlighted by decreased fibrosis and improved vascularization. Notably, echocardiographic assessments reveal that sEV treatments ameliorate diastolic dysfunction and left ventricle structural alterations typically associated with aging. Furthermore, the treatment shifts the heart metabolome towards a more youthful profile. ConclusionsThese results denote the potential of ADSC-sEVs as a novel, non-invasive therapeutic strategy to mitigate cardiac aging-associated functional decline.

physiology↗

bioRxiv2021

Small extracellular vesicles from young mice prevent frailty and improve healthspan in old mice.

Aging is associated with an increased risk of frailty, disability, comorbidities, institutionalization, falls, fractures, hospitalization, and mortality. Searching for strategies to delay the degenerative changes associated with aging and frailty is interesting. We treated old animals intravenously with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement of several functional parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function. Frailty index analysis showed that 40% of old control mice were frail, whereas none of the old ADSCs-sEVs treated mice were. Molecular and structural benefits in muscle and kidney accompanied this functional improvement. ADSCs-sEVs induced pro-regenerative effects and a decrease in oxidative stress, inflammation, and senescence markers. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSCs-sEVs and their metabolome changed to a youth-like pattern. Finally, we gained some insight into the miRNAs contained in sEVs that might be, at least in part, responsible for the effects observed. We propose that young sEVs treatment can be beneficial against frailty and therefore can promote healthy aging.

physiology↗