Biology subjects

Martin-Bermejo, M. J.

Publications and source records attributed to Martin-Bermejo, M. J..

6 recordsLinked to original sources

bioRxiv2026

Pharmacodynamic and stage-dependent therapeutic efficacy of SFRP1 neutralization in a mouse model of Alzheimer s disease

Alzheimers disease (AD) is characterized by early synaptic dysfunction followed by progressive amyloid-{beta} (A{beta}) accumulation, neuroinflammation, and cognitive decline. We previously identified Secreted Frizzled-Related Protein 1 (SFRP1) as a multifactorial contributor to AD pathogenesis and provided initial evidence that its neutralization ameliorates pathological AD-like traits in mice. Here, we evaluate the pharmacodynamics, biodistribution, and therapeutic window of an -SFRP1 monoclonal antibody (-SFRP1) in APP/PS1 mice. Pharmacokinetics and target engagement of -SFRP1 were assessed in different groups of APP/PS1 mice using biotinylated or 89Zr-labelled antibodies, with tissue distribution and -SFRP1 levels quantified by in-house ELISA or PET/CT. Therapeutic efficacy was evaluated by administering -SFRP1 or the SFRP1 inhibitor WAY-316606 at different stages of disease progression via retro-orbital injection, followed by analysis of AD-like pathology using ELISA and immunofluorescence assays followed by quantifications and statistical analysis. Using 89Zr-labelled antibodies, we show that intravenously administered -SFRP1 engages its target systemically and reaches the brain, although at substantially lower levels and with a rapid 24-hour clearance. Treatment with -SFRP1 had no apparent systemic side effects, but its therapeutic efficacy against AD-like brain pathology was strongly dependent on disease stage. While early administration reduced amyloid pathology in previous studies, treatment initiated at intermediate or advanced stages showed minimal benefit at standard doses. Higher antibody doses reduced amyloid burden and dystrophic neurites but were associated with increased mortality with time. Pharmacological inhibition of SFRP1 using a small-molecule inhibitor similarly failed to ameliorate pathology at intermediate stages. Together, these findings demonstrate that SFRP1 remains a relevant therapeutic target in AD, but its effective modulation is constrained by limited brain exposure and a narrow therapeutic window, underscoring the importance of early intervention and prompting the search for improved brain-targeted delivery strategies.

neuroscience↗

bioRxiv2025

SFRP1 drives glycolytic activation in astrocytes during neuroinflammation

Astrocytes and microglia maintain brain homeostasis and respond to inflammation through functions coordinated by molecular mediators they produce. Growing evidence shows that cellular metabolism is key to how these cells adapt to challenges. However, little is known about what drives glial metabolic reprogramming or whether molecules involved in astrocyte- microglia crosstalk also regulate this process. Here, we explored this question focusing on Secreted Frizzled-Related Protein 1 (SFRP1). SFRP1 is an astrocyte-derived factor induced by inflammatory cues and overexpressed in neurodegeneration, which fosters microglial response to inflammation through NF-{kappa}B/HIF-dependent programs. We combined mitochondrial morphometry (MitoTracker Red and MiNA analysis) with Seahorse extracellular flux assays (Mito Stress Test) to determine whether SFRP1 modulates glial bioenergetics in primary cultures of astrocytes and microglia from wild-type and Sfrp1-/- mice. We report that SFRP1 acts as a driver of astrocytic metabolic activation, preferentially enhancing glycolysis over mitochondrial respiration. This effect is most pronounced during inflammation, when oxidative phosphorylation is restricted and SFRP1 enhances glycolytic flexibility to sustain energy demands. By contrast, microglia showed the expected LPS-driven glycolytic shift with minimal dependence on SFRP1 under monoculture conditions. These findings position SFRP1 as a candidate regulator of astrocyte-centered metabolic tuning during neuroinflammation, with implications for disorders such as Alzheimers disease, in which SFRP1 is elevated.

neuroscience↗

bioRxiv2024

SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Decreased dendritic complexity and impaired synaptic function are strongly linked to cognitive decline in Alzheimers disease (AD), and precede the emergence of other neuropathological traits that establish a harmful cycle exacerbating synaptic dysfunction. SFRP1, a glial-derived protein regulating cell-cell communication, is abnormally elevated in the brain of AD patients and related mouse models already at early disease stages. Neutralization of SFRP1 activity in mice reduces the occurrence of protein aggregates, neuroinflammation and prevents the loss of synaptic long-term potentiation (LTP). In this study, we generated transgenic mice that overexpress Sfrp1 in astrocytes to investigate whether LTP loss is due to an early influence of SFRP1 on synaptic function or results from other alterations driving disease progression. We report that SFRP1-overexpressing mice show reduced dendritic complexity and spine density in dentate gyrus granule cells during early adulthood, prior to a significant deficit in LTP response and late onset cognitive impairment. Ultrastructural analysis revealed the loss of small-sized synapses and presynaptic alterations in transgenic mice. Analysis of proteomic changes points to a general decrease in protein synthesis and modifications in the synaptic proteome, particularly of proteins related to synaptic vesicle cycle and synaptic organizers, like neurexin and neuroligin. We propose a model wherein SFRP1 directly impacts on synaptic function, by increasing the availability of synaptic organizing molecules at the synapse. These observations, combined with documented SFRP1 effects on APP processing and microglial activation, imply that SFRP1 contributes to multiple pathological effects in AD, emerging as a promising therapeutic target for this devastating disease.

neuroscience↗

bioRxiv2020

Stretching of the retinal pigment epithelium contributes to zebrafish optic cup morphogenesis

The vertebrate eye primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup-shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. Here, we generated a zebrafish Tg(E1-bhlhe40:GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch into a squamous configuration, thereby matching the curvature of the underlying retina. Forced proliferation and localized interference with the RPE cytoskeleton disrupt its stretching and OV folding. Thus, extreme RPE flattening and accelerated differentiation are efficient solutions adopted by fast-developing species to enable timely optic cup formation. This mechanism differs in amniotes, in which proliferation largely drives RPE expansion with a much-reduced need of cell flattening.

developmental biology↗

bioRxiv2020

Astrocyte to microglia cross-talk in acute and chronic neuroinflammation is shaped by SFRP1

Neuroinflammation is a common feature of many neurodegenerative diseases, which fosters a dysfunctional neuron-microglia-astrocyte crosstalk that, in turn, maintains microglial cells into a perniciously reactive state that often enhance neuronal damage. The molecular components that mediate this critical communication are however not fully explored. Here, we have asked whether Secreted-Frizzled-Related-Protein-1 (SFRP1), a multifunctional regulator of cell-to-cell communication, is part of the cellular crosstalk underlying neuroinflammation. We show that in mouse models of acute and chronic neuroinflammation, astrocyte-derived SFRP1 is sufficient to promote and sustain microglial activation, and thus a chronic inflammatory state. SFRP1 allows the upregulation of components of Hypoxia Induced Factors-dependent inflammatory pathway and, to a lower extent, of those downstream of the Nuclear Factor-kappaB. We thus propose that SFRP1 acts as a critical astrocyte to microglia amplifier of neuroinflammation, representing a potential valuable therapeutic target for counteracting the harmful effect of chronic inflammation present in several neurodegenerative diseases.

neuroscience↗

bioRxiv2019

Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

Millions of individuals worldwide suffer from impaired vision, a condition with multiple origins that often impinge upon the light sensing cells of the retina, the photoreceptors, affecting their integrity. The molecular components contributing to this integrity are however not yet fully understood. Here we have asked whether Secreted Frizzled Related Protein 1 (SFRP1) may be one of such factors. SFRP1 has a context-dependent function as modulator of Wnt signalling or of the proteolytic activity of A Disintegrin And Metalloproteases (ADAM) 10, a main regulator of neural cell-cell communication. We report that in Sfrp1-/- mice, the outer limiting membrane (OLM) is discontinuous and the photoreceptors disorganized and more prone to light-induced damage. Sfrp1 loss significantly enhances the effect of the Rpe65Leu450Leu genetic variant -present in the mouse genetic background- which confers sensitivity to light-induced stress. These alterations worsen with age, affect visual function and are associated to an increased proteolysis of Protocadherin 21 (PCDH21), localized at the photoreceptor outer segment, and N-cadherin, an OLM component. We thus propose that SFRP1 contributes to photoreceptor fitness with a mechanism that involves the maintenance of OLM integrity. These conclusions are discussed in view of the broader implication of SFRP1 in neurodegeneration and aging.

neuroscience↗