Biology subjects

Sotiropoulos, I.

Publications and source records attributed to Sotiropoulos, I..

7 recordsLinked to original sources

bioRxiv2026

The loss of Tau in the adult brain triggers neuroplastic, epigenetic and behavioral deficits

INTRODUCTIONAccumulation of pathological Tau precipitates neuronal malfunction in Alzheimers disease (AD). However, the impact of loss of normal Tau function in the adult brain, independently of Tau aggregates, remains unclarified. METHODSWe used a mouse model with conditional mapt knocking-down in forebrain of 5-7 months old animals (cTau-KO), a virus-driven selective Tau knockdown in wild-types (WT) and Tau re-expression approaches, accompanied by neurostructural, epigenetic, proteomic, electrophysiological, neurochemical and behavioral analyses. RESULTSLoss of Tau in the adult brain of cTau-KOs triggers neuronal atrophy and malfunction, epigenetic as well cognitive and mood deficits. Importantly, these perturbations were confirmed by selective Tau loss in WT adult brain and reverted by Tau re-expression or pharmacologically-induced epigenetic correction in cTau-KOs. DISCUSSIONOur findings highlight the contribution of loss of normal Tau function in the adult brain malfunction that could be relevant in diverse brain pathologies beyond AD, associated to Tau and its dysfunction.

neuroscience↗

bioRxiv2024

TIA1 Mediates Divergent Inflammatory Responses to Tauopathy in Microglia and Macrophages

The RNA binding protein TIA1 is known to regulate stress responses. Here we show that TIA1 plays a much broader role in inflammatory cells, being required for the microglial sensome. We crossed TIA1 cKO mice (using a CX3CR1 driven cre element) to PS19 MAPT P301S tauopathy mice. The peripheral macrophages of TIA1 cKO mice exhibited a hyper-inflammatory phenotype with increased cytokine signaling, as expected. Surprisingly, the brains of these mice showed striking reductions in inflammation, including decreases in microglial inflammatory cytokines (TNF and IL-1{beta}) and sensome markers (CLEC7A, TREM2, ITGAX); these reductions were accompanied by corresponding decreases in tau pathology. Analysis of the brain TIA1 protein interactome identified brain selective TIA1 protein mediated pathways, including strong interactions with the microglial protein C1q, which directs pruning of dystrophic neurons. These results uncover a previously unknown regulatory role for TIA1 in microglial activation in the context of neurodegenerative disease and highlights the divergent regulation of two mononuclear phagocytic lineages: microglia and macrophages.

neuroscience↗

bioRxiv2023

Glucocorticoid stress hormones stimulate vesicle-free Tau secretion and spreading in the brain

Chronic stress and elevated levels of glucocorticoids (GCs), the main stress hormones, accelerate Alzheimers disease (AD) onset and progression. A major driver of AD progression is the spreading of pathogenic Tau protein between brain regions, precipitated by neuronal Tau secretion. While stress and high GC levels are known to induce intraneuronal Tau pathology (i.e. hyperphosphorylation, oligomerization) in animal models, their role in trans-neuronal Tau spreading is unexplored. Here, we find that GCs promote secretion of full-length, vesicle-free, phosphorylated Tau from murine hippocampal neurons and ex vivo brain slices. This process occurs via type 1 unconventional protein secretion (UPS) and requires neuronal activity and the kinase GSK3{beta}. GCs also dramatically enhance trans-neuronal Tau spreading in vivo, and this effect is blocked by an inhibitor of Tau oligomerization and type 1 UPS. These findings uncover a potential mechanism by which stress/GCs stimulate Tau propagation in AD.

neuroscience↗

bioRxiv2021

Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production

Chronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimers disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-{beta} (A{beta}) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in A{beta} overproduction remains an open question. Here, we find that hippocampal Rab35 levels are decreased not only by stress/GC but also by aging, another AD risk factor. Moreover, Rab35 negatively regulates A{beta} production by sorting amyloid precursor protein (APP) and {beta}-secretase (BACE1) out of the endosomal network, where they interact to produce A{beta}. Interestingly, Rab35 coordinates distinct intracellular trafficking events for BACE1 and APP, mediated by its effectors OCRL and ACAP2, respectively. Finally, we show that Rab35 overexpression prevents the amyloidogenic trafficking of APP and BACE1 induced by high GC levels. These studies identify Rab35 as a key regulator of APP processing and suggest that its downregulation may contribute to stress- and AD-related amyloidogenesis.

neuroscience↗

bioRxiv2019

Regulation of neuronal mRNA splicing and Tau isoform ratio by ATXN3 through deubiquitylation of splicing factors

The ubiquitylation/deubiquitylation balance in cells is maintained by deubiquitylating enzymes, including ATXN3. The precise role of this protein, mutated in spinocerebellar ataxia type 3 (SCA3), remains elusive, as few substrates for its deubiquitylating activity were identified. Here, we characterized the ubiquitome of neuronal cells lacking ATXN3, and found altered polyubiquitylation in a large proportion of proteins involved in RNA metabolism, including splicing factors. Using transcriptomic analysis and reporter minigenes we confirmed that splicing was globally altered in these cells. Among the candidate targets of ATXN3 was SRSF7 (9G8), a key regulator of MAPT (Tau) exon 10 splicing. Loss-of-function of ATXN3 led to reduced SRSF7 levels and a deregulation of MAPT exon 10 splicing, resulting in a decreased 4R/3R-Tau ratio. Similar alterations were found in cellular models of expanded polyQ ATXN3 and SCA3 patient brains, pointing to a relevant role of this mechanism in SCA3, and establishing a previously unsuspected link between two key proteins involved in different neurodegenerative disorders.

neuroscience↗

bioRxiv2018

MORPhA Scale: behavioral and electroencephalographic validation of a rodent anesthesia scale

Degree of anesthesia in laboratory rodents is normally evaluated by testing loss of reflexes. While these are useful endpoint assessments, they are of limited application to study induction/reversal kinetics or factors affecting individual susceptibility (e.g. sex or age). We developed and validated a grading system for a temporal follow up of anesthesia. The Minho Objective Rodent Phenotypical Anesthesia (MORPhA) scale was tested in mice and rats anaesthetized with a mixture of ketamine/dexmedetomidine (ket/dex - 3 doses). The scale comprises 12 behavioral readouts organized in 5 stages - (i) normal/(ii) hindered voluntary movement, elicited response to (iii) non-noxious/(iv) noxious stimuli and (v) absence of response - evaluated at regular time points. Progression across stages was monitored by electroencephalography (EEG) in rats during anesthesia induction and reversal (atipamezole) and during induction with a second anesthetic drug (pentobarbital). Higher anesthetic doses decreased the time to reach higher levels of anesthesia during progression, while increasing the time to regain waking behavior during reversal, in mice and in rats. A regular decrease in high frequencies (low and high gamma) power was observed as the MORPhA score increased during anesthesia induction, while the opposite pattern was observed during emergence from anesthesia through reversion of dex effect. The devised anesthetic scale is of simple application and provides a semi-quantifiable readout of anesthesia induction/reversal.

neuroscience↗

bioRxiv2018

Endo-lysosomal sorting and degradation of Tau mediates glucocorticoid-driven hippocampalmalfunction

Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimers disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD, and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

neuroscience↗