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Valente, D.

Publications and source records attributed to Valente, D..

7 recordsLinked to original sources
bioRxiv2025

Non-neuronal, TGF-β- extracellular matrix restructuring promotes neurodegeneration in a PSP-Richardson syndrome model

Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a rapidly progressive tauopathy lacking effective therapies. Although tau aggregation is a defining feature, the initiating mechanisms remain elusive. Here we used patient-derived induced pluripotent stem cell midbrain organoids, integrating single-cell transcriptomics, bulk RNA profiling, and quantitative proteomics, to dissect early pathogenic events. We identified vascular leptomeningeal-like cells (VLMCs) as the first altered population, exhibiting TGF-{beta}-driven extracellular matrix (ECM) remodeling enriched in collagens, integrins, and TGFBI. The resulting pathological ECM increased stiffness, induced integrin clustering, and activated RhoA-ROCK-mediated cytoskeletal disorganization. These changes sustained PI3K-AKT and MAPK-ERK signaling, suppressed PP2A, hyperactivated mTOR, and impaired autophagy, culminating in tau hyperphosphorylation and mislocalization. Pharmacological inhibition of TGF-{beta}, AKT, ERK, or mTORC1 restored autophagic flux, reduced tau burden, and rescued neuronal architecture. Our findings establish non-neuronal, matrix-producing niche cells as upstream drivers of tauopathy and reveal TGF-{beta}-mediated ECM restructuring as a mechanochemical trigger of neurodegeneration, opening multiple therapeutic avenues for PSP-RS and related tauopathies.

neuroscience↗
bioRxiv2025

Insight into human photoreceptor function: modeling optoretinographic responses to diverse stimuli

Optoretinography is an emerging method for detecting and measuring functional responses from neurons in the living human retina. Its potential applications are significant and broad, spanning clinical assessment of retinal disease, investigation of fundamental scientific questions, and rapid evaluation of experimental therapeutics for blinding retinal diseases. Progress in all these domains hinges on the development of robust methods for quantifying observed responses in relation to visible stimuli. In this work, we describe a novel optoretinographic imaging platform-full-field swept-source optical coherence tomography with adaptive optics, measure cone responses in two healthy volunteers to a variety of stimulus patterns, and propose a simple model for predicting and quantifying responses to those stimuli. TeaserThe function of human retinal neurons is quantified by the light they reflect, opening a new frontier in visual health

physiology↗
bioRxiv2024

Mosaic midbrain organoids: a new tool to study Progressive Supranuclear Palsy and advancing clinical neurology research

Progressive supranuclear palsy (PSP) is a severe neurodegenerative disease pathologically characterized by intracellular tangles of hyperphosphorylated tau protein, widely distributed across the neocortex, basal ganglia, and midbrain. Developing effective drugs for PSP presents challenges due to its complex underpinning mechanism and the absence of robust human models that accurately recapitulate biochemical and pathological features of the disease phenotype. Brain organoids have recently emerged as a three-dimensional tissue culture platform to study brain development and pathology. Here, we present a novel induced pluripotent stem cell (iPSC)-derived mosaic midbrain organoid (mMOs) system from four patients with progressive supranuclear palsy-Richardson syndrome (PSP-RS), aimed at reproducing key molecular disease features while reducing variability across organoids derived from different iPSC donors. The PSP-RS 3D model exhibited accumulation of hyperphosphorylated tau protein, predominance of 4R-tau, increased GFAP-positive cells, and PSP-associated histological alterations compared to organoids derived from healthy donors. Pathologically, diseased mMOs showed typical neurofibrillary tangles and tufted-shaped astrocytes, and poorly branched processes of Tyrosine Hydroxylase-immunoreactive cells with thin terminal branches. Our results suggest that mMOs represent a valuable experimental model for PSP research and hold great promise for future identification of new therapeutic targets for progressive supranuclear palsy. O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/597136v1_unfig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@8b2942org.highwire.dtl.DTLVardef@41e3baorg.highwire.dtl.DTLVardef@1cddaeeorg.highwire.dtl.DTLVardef@1e0716c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗
bioRxiv2022

Velocity-based optoretinography for clinical applications

Optoretinography (ORG) is an emerging tool for testing neural function in the retina. Unlike existing methods, it is noninvasive, objective, and provides information about retinal structure and function at once. As such, it has great potential to transform ophthalmic care and clinical trials of novel therapeutics designed to restore or preserve visual function. Recent efforts have demonstrated the feasibility of the ORG using state-of-the-art optical coherence tomography systems. These methods measure the stimulus-evoked movement of subcellular features in the retina, using the phase of the reflected light to monitor their position. Here we present an alternative approach that monitors the velocity of these features instead. This conceptual shift has significant implications for the nascent field of optoretinography. By avoiding the need to track specific cells over time, it obviates costly and laborious aspects of the position-based approaches, such as adaptive optics, digital aberration correction, real-time tracking, and three-dimensional segmentation and registration. We used this novel velocity-based approach to measure the photoreceptor ORG responses in three healthy subjects. The resulting responses were reproducible and exhibited dependence on dose and retinal eccentricity. The position of the relevant structures was reconstructed through numerical integration of velocity.

neuroscience↗
bioRxiv2021

Investigating the causes of stimulus-evoked changes in cone reflectance using a combined adaptive optics SLO-OCT system

In vivo functional imaging of human photoreceptors is an emerging field, with compelling potential applications in basic science, translational research, and clinical management of ophthalmic disease. Measurements of light-evoked changes in the photoreceptors has been successfully demonstrated using adaptive optics (AO) coherent flood illumination (CFI), AO scanning light ophthalmoscopy (SLO), AO optical coherence tomography (OCT), and full-field OCT with digital AO (dAO). While the optical principles and data processing of these systems differ greatly, and while these differences manifest in the resulting measurements, we believe that the underlying physiological processes involved in each of those techniques are likely the same. AO-CFI and AO-SLO systems are more widely used than OCT systems. However, those systems produce only two-dimensional images and so, less can be said about the anatomical and physiological origins of the observed signal. OCT signal, on the other hand, provides 3D imaging but at a cost of high volume of data, making it impractical to clinical purposes. In light of this, we employed a combined AO-OCT-SLO system-with point-for-point correspondence between the OCT and SLO images-to measure functional responses simultaneously with both and investigate SLO retinal functional biomarkers based on OCT response. The resulting SLO images reveal reflectance changes in the cones which are consistent with those previously reported using AO-CFI and AO-SLO. The resulting OCT volumes show phase changes in the cone outer segment (OS) consistent with those previously reported by us and others. We recapitulate a model of the cone OS previously proposed to explain AO-CFI reflectance changes, and show how this model can be used to predict the signal in AO-SLO. The limitations of the model is also discussed in this manuscript.

bioengineering↗
bioRxiv2020

Kilohertz retinal FF-SS-OCT and flood imaging with hardware-based adaptive optics

A retinal imaging system was designed for full-field (FF) swept-source (SS) optical coherence tomography (OCT) with cellular resolution. The system incorporates a real-time adaptive optics (AO) subsystem and a very high speed CMOS sensor, and is capable of acquiring volumetric images of the retina at rates up to 1 kHz. While digital aberration correction (DAC) is an attractive potential alternative to AO, it has not yet been shown to provide resolution of cones in the fovea, where early detection of functional deficits is most critical. Here we demonstrate that FF-SS-OCT with hardware AO permits resolution of foveal cones, with volume rates adequate to measure light-evoked changes in photoreceptors. With the reference arm blocked, the system can operate as kilohertz AO flood illumination fundus camera with adjustable temporal coherence and is expected to allow measurement of light-evoked changes caused by common path interference in photoreceptor outer segments (OS). In this work, we describe the systems optical design, characterize its performance, and demonstrate its ability to produce images of the human photoreceptor mosaic.

bioengineering↗