Biology subjects

Sotty, F.

Publications and source records attributed to Sotty, F..

4 recordsLinked to original sources

bioRxiv2025

Transferrin receptor-binding blood-brain barrier shuttle enhances brain delivery and efficacy of a therapeutic anti-Abeta antibody

Transferrin receptor-1 (TfR1) transcytosis-mediated delivery of therapeutic monoclonal antibodies across the blood-brain barrier (BBB) is a promising concept in drug development for CNS disorders. We sought to investigate brain delivery and efficacy of Aducanumab (Adu), an anti-A{beta} antibody, when fused to a mouse TfR1-binding Fab fragment as BBB shuttle (TfR1-Adu). Automated 3D light sheet fluorescence imaging coupled with computational analysis was applied to evaluate drug IgG distribution and plaque counts throughout the intact brain of transgenic APP/PS1 mice. TfR1-Adu demonstrated enhanced brain delivery and more homogeneous distribution after both acute and chronic dosing in transgenic APP/PS1 mice compared with unmodified Adu. Also, importantly, only unmodified Adu showed perivascular labelling. While high-dose Adu promoted A{beta} plaque depletion in multiple brain regions, similar plaque-clearing efficacy was achieved with a five-fold lower dose of TfR1-Adu. Furthermore, low-dose TfR1-Adu demonstrated greater capacity to reduce congophilic plaque burden. Collectively, these observations strongly support the applicability of TfR1-enabled BBB shuttle strategies to improve brain delivery and plaque-clearing efficacy while mitigating the risk of vascular-associated amyloid-related imaging abnormalities (ARIA) adverse effects associated with current A{beta} immunotherapeutics.

neuroscience↗

bioRxiv2022

Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model

Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimers Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Spectral power analysis revealed a reduction of basal theta oscillations in rTg4510 mice. Enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol was further indicated by an increase in theta power and higher number of absence-like seizures in rTg4510 compared to control mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as a biomarker candidate in early stages of neurodegenerative tauopathies.

neuroscience↗

bioRxiv2022

Visual evoked potentials as an early-stage biomarker in the rTg4510 tauopathy mouse model

Tauopathies such as Alzheimers Disease (AD) and frontotemporal dementia (FTD) are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Early pathophysiological and functional changes related to neurofibrillary tangles formation are considered to occur prior to extensive neurodegeneration. Hyperphosphorylated tau has been detected in postmortem retinas of AD and FTD patients, and the visual pathway is an easily accessible system in a clinical setting. Hence, assessment of the visual function may offer the potential to detect consequences of early tau pathology in patients. In this study we explored the association between the visual system and functional consequences of tau pathology progression using a tauopathy rTg4510 mouse model. To this end, we recorded full-field electroretinography and visual evoked potentials in anesthetized and awake states at different ages. While retinal function remained mostly intact within all the age groups investigated, we detected significant changes in amplitudes of visual evoked potential responses in young rTg4510 mice exhibiting early tau pathology prior to neurodegeneration. These functional alterations in the visual cortex were positively correlated with pathological tau levels. Our findings suggest that visual processing could be useful as a novel electrophysiological biomarker for early stages of tauopathy.

neuroscience↗

bioRxiv2018

Long-term exposure to PFE-360 in the AAV-α-synuclein rat model: findings and implications

Significance statementTreatment of Parkinsons disease is reliant on symptomatic treatments, without any option to slow or halt disease progression. Mutations in LRRK2 and -synuclein are known risk factors for Parkinsons disease. Presence of -synuclein aggregates at autopsies in both idiopathic and most G2019S cases is suggestive of a common disease pathogenesis. LRRK2 and -synuclein interaction is hypothesized to play a pivotal role in the pathological mechanisms and inhibitors of LRRK2 are investigated as novel disease modulatory treatments in the clinic. However, preclinical in vivo evidence of a beneficial effect of LRRK2 inhibition is mixed and limited. This study increases our understanding of LRRK2 as a mediator of neuronal dysfunction and the potential of LRRK2 as a promising target in PD.

neuroscience↗