Biology subjects

Potier, M.-C.

Publications and source records attributed to Potier, M.-C..

14 recordsLinked to original sources

bioRxiv2026

Differential endothelial cell remodeling in Down syndrome and APP duplication drives distinct blood brain barrier dysfunction

An extra copy of the amyloid precursor protein gene (APP) is present in Down syndrome (DS) and APP duplication (APPdup), increasing the risk of Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). However, we reported greater vascular A{beta} deposition in APPdup than in DS with AD, suggesting that other triplicated chromosome 21 genes may mitigate CAA severity. We investigated endothelial cell (EC) function and blood brain barrier (BBB) integrity in DS and APPdup using human induced pluripotent stem cell-derived ECs (iECs), assessing their morphology, junctional proteins, A{beta} peptide secretion, barrier function, and transcriptomic profiles. Both DS and APPdup iECs secreted more A{beta}40 A{beta}42 compared with their respective isogenic controls but exhibited distinct A{beta} peptide profiles. DS iECs showed increased junctional protein expression and reduced permeability, whereas APPdup iECs displayed increased permeability. Transcriptomic analysis revealed extensive dysregulation in DS iECs, with enrichment of junctional, adhesion, angiogenic, immune, and apoptosis pathways, and reduced cell-cycle, proliferative, and membrane-targeting signatures. APPdup iECs showed milder changes, including impaired protein targeting and reduced adhesion-related pathways. Despite comparable APP dosage, DS iECs maintained greater junctional integrity and lower permeability than APPdup iECs, potentially contributing to differential CAA vulnerability. However, impaired proliferation and altered angiogenesis may reduce BBB resilience during ageing.

neuroscience↗

bioRxiv2026

Differential efficacy of α5IA in the Dp(16)1Yey mouse model of Down syndrome: implications for translational research

Cognitive impairments significantly impact the daily life of people with Down syndrome (DS). Overinhibition mediated by interneurons in the central nervous system was proposed as a key pathophysiological mechanism. Previous studies demonstrated cognitive rescue in the Ts65Dn mouse model using 5IA, a negative allosteric modulator of the 5 subunit-containing GABAA receptors. Here, we evaluated the effect of this drug in a mouse model carrying a more accurate duplication of the orthologous region to the human chromosome 21, namely the Dp(16)1Yey mouse model. First, we expanded the phenotypic characterization of Dp(16)1Yey mice using translationally more relevant behavioral tests. We confirmed spatial memory deficits in Dp(16)1Yey mice in the Barnes maze, and highlighted robust learning deficits in the pattern dissociation task and impairments in motor coordination. Next, we evaluated the effect of 5IA treatment on cognitive and motor performance. While 5IA treatment improved motor coordination in the Dp(16)1Yey mice, it failed to restore cognitive performance in the Barnes maze or in the pattern dissociation task. These findings could suggest divergent pathophysiological mechanisms between the Dp(16)1Yey and the Ts65Dn models. Potentially, it could explain the limited efficacy of similar pharmacological intervention in clinical trials for DS. Further preclinical studies should prioritize refined behavioral paradigms and probably the use of more complex DS models to enhance the translational potential of candidate therapies.

neuroscience↗

bioRxiv2026

Obesity-related alterations in plasma metabolomics and fecal microbiota in Down syndrome Dp(16)1Yey mice

Background/ObjectivesIndividuals with Down syndrome (DS) are at increased risk of obesity and metabolic comorbidities, yet the mechanisms underlying these conditions remain unclear. Here we investigated how DS-associated genetic condition interacts with diet and metabolic pathways in the Dp(16)1Yey mouse model of DS. MethodsUntargeted plasma metabolomics was performed in Dp(16)1Yey and control mice, subjected to either control or high-fat diet (HFD). Raw data were processed, and features were annotated. Statistical analyses were conducted in R, and pathway analysis was performed with MetaboAnalyst v5.0. Fecal microbiome was obtained using 16SrRNAseq and analyzed using phyloseq in R. ResultsDiet exerted the strongest effect on mice plasma metabolome, followed by sex and genotype. Seventy-five diet-responsive metabolites were enriched in amino acid and nucleotide metabolism. Genotype-driven changes affected 34 metabolites, notably impacting amino acid and taurine-hypotaurine metabolism. Fifty-six sex-associated metabolites highlighted disruptions in aromatic amino acid biosynthesis and pyrimidine metabolism. A significant Diet*Genotype interaction was observed for five metabolites, including a marked reduction in the microbiota-derived metabolite 3-indolepropionic acid (IPA) in Dp(16)1Yey mice on HFD. Both genotype and diet exerted pronounced effects on fecal microbiome with selective depletion of the IPA-producing Clostridia in Dp1Yey mice under HFD. ConclusionSegmental trisomy in Dp(16)1Yey mice modulates the host metabolic response to dietary fat, partly through microbiota-derived metabolites such as IPA. These findings highlight the importance of genotype, diet, and microbiome interactions in shaping metabolic disease risk in DS and point toward microbiota-targeted dietary interventions.

neuroscience↗

bioRxiv2026

Toll-like receptor 9 contributes in microglial activation and lysosomal dysfunction to promote Alzheimer disease

Toll like receptor 9 (TLR9) is an endosomal-lysosomal innate immune receptor which recognizes microbial and host-derived double-stranded DNA (dsDNA) to induce cellular immunity. TLR9 pathway has been implicated in Alzheimers disease (AD) pathology via its ability to modulate peripheral immune cells but its exact role in the central nervous system (CNS) remains unclear. Here we show that extranuclear dsDNA accumulating in human AD brain and in a mouse model of AD, together with microglia around amyloid-{beta} (A{beta}) plaques stimulates TLR9 in vitro. Loss of TLR9 inhibits the transition of homeostatic microglia to reactive microglia, a cell type associated with a chronic pro-inflammatory state, promoting their reprogramming into an anti-inflammatory state, thereby restoring lysosomal integrity required for A{beta} peptides degradation. Predisposition to lysosome permeabilization could be mimicked with repeated TLR9 stimulation using CpG-A ODNs in a human microglial cell line and was rescued with TLR9 inhibition. Furthermore, lack of TLR9 protects mice developing AD from cognitive defects and neuronal loss. A{beta} pathology is also reduced specifically in male mice. Altogether, our results have identified a critical role of TLR9 in AD, where it modulates microglial activation and lysosome function to interfere with the progression of AD. These findings suggest that targeting TLR9 signaling and lysosomal function may be a relevant strategic approach to reduce AD pathology.

immunology↗

bioRxiv2025

Large extracellular vesicles containing mitochondria (EVMs) derived from Alzheimer disease cells harbor pathologic functional and molecular profiles and spread mitochondrial dysfunctions

In addition to small extracellular vesicles known as exosomes, cells release large extracellular vesicles containing mitochondria (EVMs). However, the molecular and functional characteristics of EVMs, as well as the impact of EVM secretion on the spreading of mitochondrial dysfunction between cells, remain unknown in the context of Alzheimers Disease (AD). Here, we provide an ultrastructural, biochemical, and functional characterization of EVMs isolated from cells expressing the amyloid precursor protein (APP) with the familial Swedish mutation (APPswe). We identified differential proteomic and lipidomic signatures in APPswe-derived EVMs compared to control EVMs and revealed a specific proteomic profile in EVMs isolated from conditioned media of fibroblasts from AD patients at the prodromal stage of the disease. Our findings show that APP-C terminal fragments (APP-CTFs) pathogenic accumulation in cells potentiates EVM secretion through the budding of the plasma membrane. We lastly demonstrated that APP-CTFs loaded EVMs are active carriers of dysfunctional mitochondria that transfer mitochondrial pathology to naive control recipient cells.

neuroscience↗

bioRxiv2024

Mutations in PSEN1 predispose inflammation in an astrocyte model of familial Alzheimer's disease through disrupted regulated intramembrane proteolysis

Mutations in PSEN1 cause familial Alzheimers disease with almost complete penetrance. Age at onset is highly variable between different PSEN1 mutations and even within families with the same mutation. Current research into late onset Alzheimers disease implicates inflammation in both disease onset and progression. PSEN1 is the catalytic subunit of {gamma}-secretase, responsible for regulated intramembrane proteolysis of numerous substrates that include cytokine receptors. For this reason, we tested the hypothesis that mutations in PSEN1 impact inflammatory responses in astrocytes, thereby contributing to disease progression. Here, using iPSC-astrocytes, we show that PSEN1 is upregulated in response to inflammatory stimuli, and this upregulation is disrupted by pathological PSEN1 mutations. Using transcriptomic analyses, we demonstrate that PSEN1 mutant astrocytes have an augmented inflammatory profile in their basal state, concomitant with an upregulation of genes coding for regulated intramembrane proteolytic and robust activation of JAK-STAT signalling. Using JAK-STAT2 as an example signalling pathway, we show altered phosphorylation cascades in PSEN1 mutant astrocytes, reinforcing the notion of altered cytokine signalling cascades. Finally, we use small molecule modulators of {gamma}-secretase to confirm a role for PSEN1/{gamma}-secretase in regulating the astrocytic response to inflammatory stimuli. Together, these data suggest that mutations in PSEN1 enhance cytokine signalling via impaired regulated intramembrane proteolysis, thereby predisposing astrocytic inflammatory profiles. These findings support a two-hit contribution of PSEN1 mutations to fAD pathogenesis, not only impacting APP and A{beta} processing but also altering the cellular response to inflammation.

neuroscience↗

bioRxiv2023

Mitochondria alterations in fibroblasts from sporadic Alzheimer's disease (AD) patients correlate with AD-related clinical hallmarks

INTRODUCTIONMitochondria dysfunctions are key features in Alzheimers disease (AD). The occurrence of these disturbances in AD patients peripheral cells and their potential correlation with disease progression are under investigated. METHODSWe studied mitochondrial structure, function and mitophagy in fibroblasts including healthy volunteers and AD patients at the prodromal (AD-MCI) or demented (AD-D) stages. We carried out correlation studies with clinical cognitive scores, A{beta} plaques burden and the accumulation of peripheral amyloid precursor protein C-terminal fragments (APP-CTFs). RESULTSWe unveiled progressive alteration of mitochondria structure as well as specific mitochondrial dysfunctions signatures in AD-MCI and AD-D fibroblasts and show defective mitophagy and autophagy linked to impaired lysosomal activity in AD-D fibroblasts. We reported on significant correlations of a subset of these dysfunctions with cognitive decline, AD-related clinical hallmarks and peripheral APP-CTFs accumulation. DISCUSSIONThis study emphasizes the potential use of peripheral cells for investigating AD pathophysiology and likely diagnosis.

cell biology↗

bioRxiv2022

Ts66Yah, a refined Ts65Dn DS mouse model, unravels genetic interaction between regions homologous to Human chromosome 21 and the Scaf8-Pde10a genetic interval.

Down syndrome is caused by trisomy of human chromosome 21 (Hsa21). The understanding of phenotype-genotype relationships, the identification of driver genes and various proof-of-concepts for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to the human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16 (Mmu16), homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 (Mmu17) fromPisd-ps2/Scaf8 to Pde10a, containing 46 genes, not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CrispR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures, were changed suggesting genetic interactions between the Mir155-Zbtb21 and the Scaf8-Pde10a interval. Thus, Ts66Yah mice have a stronger construct and face validity for mimicking consequences of DS genetic overdosage. Furthermore, this report is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21.

genetics↗

bioRxiv2022

Theta band-power shapes amyloid-driven longitudinal EEG changes in pre-clinical Alzheimer's Disease

Alzheimers Disease (AD) includes progressive symptoms spread along a continuum of pre-clinical (pre-AD) and clinical stages. Pre-AD refers to cognitively healthy individuals with presence of positive pathophysiological biomarkers of AD (i.e., markers of amyloidopathy and tauopathy). Although numerous studies uncovered the neuro-cognitive changes of AD, very little is known on the natural history of brain lesions and modifications of brain networks of pre-AD. To address this issue, we analysed resting-state EEG data of 318 cognitively healthy individuals with subjective memory complains from the INSIGHT-preAD cohort at the time of their first visit (M0) and two-years later (M24). Using 18F-florbetapir PET-scanner, subjects were stratified between amyloid positive (A-; n=230) and amyloid negative (A+; n=88) groups. Differences between A+ and A- individuals were estimated at source level in each band of the EEG power spectrum. At M0, we found an increase of theta-band power in the mid-frontal cortex in A+ compared to A-. No significant association was found between mid-frontal theta power and the individuals cognitive performance. While the very same effect was not replicated at M24, theta-band power increased in A+ relative to A- individuals in the posterior cingulate cortex and the pre-cuneus. Furthermore, alpha band revealed a peculiar decremental trend in posterior brain regions in the A+ relative to the A- group only at M24. These results provide the first source-level longitudinal evidence on the impact of brain amyloidosis on the EEG dynamics of a large-scale, monocentric cohort of pre-AD. Theta-band power increase over the mid-frontal and mid-posterior cortices suggests an hypoactivation of the default-mode network in individuals at-risk of AD and a non-linear longitudinal progression of the AD-spectrum.

neuroscience↗

bioRxiv2022

3D-imaging reveals conserved cerebrospinal fluid drainage via meningeal lymphatic vasculature in mice and humans

Meningeal lymphatic vessels (MLVs) contribute to waste product elimination and immune surveillance in brain tissues. MLVs were identified in the dorsal and caudo-basal regions of the dura mater, where they ensure the clearance of cerebrospinal fluid (CSF). Whether MLVs exist in the complex anterior part of the murine and human skull, and how they connect with the glymphatic system and extracranial lymphatic vasculature remained unclear. Here, we generated three-dimensional (3D) maps of MLV drainage by light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations following fluorescent OVA-A555 tracer injections into the CSF. In humans, we performed real-time magnetic resonance vessel wall imaging (MR-VWI) after systemic gadobutrol injections. We observed a conserved 3D-anatomy of MLVs in mice and humans, and we discovered an extended anterior network around the dural cavernous sinus including multiple capillary beds and exit routes through the foramina of emissary veins. MR-VWI may provide a diagnostic tool for patients with CSF drainage defects and neurological diseases. Short abstractWe established the 3D-anatomy of meningeal lymphatic vasculature and associated CSF drainage by postmortem light-sheet imaging in mice and by real-time magnetic resonance imaging in humans, demonstrating conserved lymphatic circuitries in contact with dural venous sinuses.

neuroscience↗

bioRxiv2021

Molecular signature and target-specificity of inhibitory circuits formed by Martinotti cells in the mouse barrel cortex

In the neocortex, fast synaptic inhibition orchestrates both spontaneous and sensory-evoked activity. GABAergic interneurons (INs) inhibit pyramidal neurons (PNs) directly, modulating their output activity and thus contributing to balance cortical networks. Moreover, several IN subtypes also inhibit other INs, forming specific disinhibitory circuits, which play crucial roles in several cognitive functions. Here, we studied a homogeneous subpopulation of somatostatin (SST)-positive INs, the Martinotti cells (MCs) in layer 2/3 of the mouse barrel cortex (both sexes). MCs are a prominent IN subclass inhibiting the distal portion of PN apical dendrites, thus controlling dendrite electrogenesis and synaptic integration. Yet, it is poorly understood whether MCs inhibit other elements of the cortical circuits, and the connectivity properties with non-PN targets are unknown. We found that MCs have a strong preference for PN dendrites, but they also considerably connect with parvalbumin (PV)-positive, vasoactive intestinal peptide (VIP)-expressing and layer 1 (L1) INs. Remarkably, GABAergic synapses from MCs exhibited clear cell-type-specific short-term plasticity. Moreover, whereas the biophysical properties of MC-PN synapses were consistent with distal dendritic inhibition, MC-IN synapses exhibited characteristics of fast perisomatic inhibition. Finally, MC-PN connections used 5-containing GABAARs, but this subunit was not expressed by the other INs targeted by MCs. We reveal a specialized connectivity blueprint of MCs within different elements of superficial cortical layers. In addition, our results identify 5-GABAARs as the molecular fingerprint of MC-PN dendritic inhibition. This is of critical importance, given the role of 5-GABAARs in cognitive performance and their involvement in several brain diseases. Significance statementMartinotti cells (MCs) are a prominent subclass of SST-expressing GABAergic INs, specialized in controlling distal dendrites of PNs and taking part in several cognitive functions. Here we characterize the connectivity pattern of MCs with other INs in the superficial layers (L1 and L2/3) of the mouse barrel cortex. We found that the connectivity pattern of MCs with PNs as well as PV, VIP and L1 INs exhibit target-specific plasticity and biophysical properties. The stark specificity of 5-GABAARs at MC-PN synapses, and the lack or functional expression of this subunit by other cell types, define the molecular identity of MC-PN connections and the exclusive involvement of this outstanding inhibitory circuits in 5-dependent cognitive tasks.

neuroscience↗

bioRxiv2020

Mutations in the juxtamembrane segment of the cholesterol-binding site of APP alter its processing and promotes production of shorter, less toxic Aβ peptides.

BackgroundThe brains of patients with Alzheimers disease (AD) reveal increased cellular membrane levels of cholesterol. Correspondingly, we previously showed that elevating levels of membrane cholesterol in neuronal cultures recapitulates early AD phenotypes including excessive cleavage of amyloid {beta} (A{beta}) peptides from the amyloid precursor protein (APP). Here we aimed to evaluate how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of APP regulates its processing. MethodsWe generated seven single and two double APP mutants at amino acid positions 22, 26, 28, 29, 33, 39 of the A{beta} sequence changing the charge and/or hydrophobicity of the targeted amino acids. HEK293T cells were transfected with APP constructs and secreted A{beta} peptides were measured using ELISA and mass spectrometry (MS). APP processing in normal and high cholesterol condition, and endocytosis were assessed in stably expressing APPwt and APPK28A HEK293T clones. Finally, we measured the binding of synthetic peptides derived from the A{beta} sequence to cholesterol-rich exosomes purified from control HEK293T cells. ResultsMost mutations triggered a reduction in the production of A{beta}40 and A{beta}42 peptides, whereas only juxtamembrane mutants resulted in the generation of shorter A{beta} peptides. We confirmed by mass spectrometry this specific change in the profile of secreted A{beta} peptides for the most characteristic APPK28A mutant. A transient increase of plasma membrane cholesterol enhanced the production of A{beta}40 by APPWT, an effect absent with APPK28A. The enzymatic activity of -, {beta}- and {gamma}-secretases remained unchanged in cells expressing APPK28A. Similarly, APPK28A subcellular localization in early endosomes did not differ to APPWT. Finally, WT but not CBS mutant A{beta} derived peptides bound to cholesterol-rich exosomes. ConclusionsTaken together, these data reveal a major role of the juxtamembrane region of APP in binding to cholesterol and accordingly in the regulation of APP processing. Binding of cholesterol to K28 could staple APP to the juxtamembrane region thereby permitting access to {gamma}-secretase cleavage at positions 40-42. The APPK28 mutant would lie deeper in the membrane, facilitating the production of shorter A{beta} peptides and unveiling this specific region as a novel target for reducing the production of toxic A{beta} species.

neuroscience↗

bioRxiv2020

Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin

Studies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the evidence has not been consistent. In particular, signaling pathways controlling APP transport to the synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), the scaffolding protein involved in Huntingtons disease, regulates neuritic transport of APP, we used a microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the pre- and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic density. Ablating in vivo HTT phosphorylation in APPPS1 mice, which overexpress APP, reduced presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis.

neuroscience↗

bioRxiv2020

Alterations of specific inhibitory circuits of the prefrontal cortex underlie abnormal network activity in a mouse model of Down syndrome

Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration of their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying of cognitive dysfunctions in DS.

neuroscience↗