Biology subjects

Buee, L.

Publications and source records attributed to Buee, L..

At least 19 recordsLinked to original sources

bioRxiv2026

A proline-rich-domain-binding single domain antibody selectively inhibits RNA-induced liquid-liquid phase separation of tau

Liquid-liquid phase separation (LLPS) mediates the formation of biomolecular condensates, which organize cellular processes such as synaptic plasticity and stress response. The neuronal microtubule-associated protein tau undergoes LLPS under specific conditions, regulating synaptic vesicle clustering and microtubule dynamics. In vitro, tau LLPS is induced by cofactors such as polyethylene glycol (PEG) or RNA, mainly via weak multivalent electrostatic interactions. However, the molecular mechanisms governing the formation of tau LLPS, including domain specific contribution, remain unclear. In this study, we used eight single-domain antibodies (VHHs), targeting six distinct short sequences of tau, to explore the mechanisms of tau LLPS in vitro. By combining several biophysical methods, we evaluated the effect of each anti-tau VHH on tau LLPS with two main LLPS inducers, PEG (molecular crowding) and RNA (complex coacervation). With PEG as an inducer, all VHHs targeting tau enhanced tau LLPS formation, regardless of their affinity for tau. With RNA as an inducer, the effect of the VHHs was mixed: VHHs targeting the C-terminal domain promoted condensation, while VHH B1-1, which binds the proline-rich domain (PRD; including residues (221REPKKVAVVRTP232), abolished droplet formation. NMR and surface plasmon resonance confirmed 1 to 1 binding of VHH B1-1 to the PRD, and competition assays with a PRD peptide restored LLPS, demonstrating mechanistic specificity. This result underscores the importance of this region in tau LLPS formation. Our findings provide domain-resolved insights into the regulation of tau LLPS and demonstrate the potential of VHHs as tools to selectively modulate biomolecular condensates in physiological and pathological contexts.

biochemistry↗

bioRxiv2025

N-terminally acetylated Met11-Tau: a new pathological truncated Tau species with functional relevance in Alzheimer Disease

Neurodegenerative diseases like Alzheimers disease (AD) are characterized by progressive accumulation of pathological Tau proteins. Among the diverse Tau species, truncated variants are emerging as key contributors, yet their identity remains elusive, particularly for the N-terminal truncated ones. The present study identifies and characterizes a novel N-terminally truncated and N-alpha-acetylated form of the Tau protein. Using a newly developed antibody specifically targeting this truncated variant, we demonstrate that this species accumulates early in degenerating neurons in both transgenic mouse models of AD-related Tau pathology and post-mortem brain tissues from AD patients. Importantly, in vivo functional experiments reveal that expression of this truncated Tau species exacerbates Tau pathology, whereas targeted immunotherapeutic with the specific antibody significantly reduces pathological Tau accumulation and prevents associated memory impairments. These findings position this newly identified Tau variant as both a marker of neurofibrillary degeneration and a pathogenic driver of neurodegeneration and supports its potential as a therapeutic target in Tau-related disorders, notably AD.

neuroscience↗

bioRxiv2025

AETA peptide drives Alzheimer's disease signature of synapse dysfunction

Alzheimers disease (AD), the leading cause of dementia, is characterized by early synaptic dysfunction that precedes overt cognitive decline. While amyloid-{beta} and Tau remain central to AD pathogenesis, molecular triggers of synapse weakening remain unclear. Here, we investigated AETA, a novel brain-secreted peptide derived from amyloid precursor protein (APP), as a potential mediator of synapse dysfunction in AD. We previously identified AETA as a unique modulator of NMDA receptor activity in the healthy brain; however, its role in AD etiology was yet to be explored. Post-mortem analyses of human hippocampal and prefrontal cortex tissues revealed significantly elevated AETA levels in AD patients, particularly in females. To further explore the contribution of AETA to AD synaptic pathology, we analyzed a new mouse model, the AETA-m mouse, exhibiting chronically increased brain AETA expression. Hippocampi of female AETA-m mice display an increase in the number of astrocyte and microglia, but no overt neuroinflammation. RNA sequencing of female AETA-m hippocampi revealed alterations in synaptic gene expression that closely paralleled those observed in vulnerable human AD brain regions, most notably in the hippocampus. These two phenotypes were absent in males. Functionally, hippocampal neurons from AETA-m mice displayed impaired NMDA receptor signaling, dendritic spine loss, and memory deficits especially in females, mirroring early AD-associated synaptic dysfunction. Together, these findings identify AETA as a novel key contributor of synaptic vulnerability in AD and associated memory processing, especially in females. Targeting AETA signaling may therefore offer new therapeutic avenues for preventing or mitigating synaptic and cognitive decline in AD.

neuroscience↗

bioRxiv2025

Sex-dependent effects of maternal high-fat diet during lactation in adult THY-Tau22 mice offspring

The perinatal environment has been suggested to participate to the development of tauopathies and Alzheimers disease but the molecular and cellular mechanisms involved remain contradictory and under-investigated. Here, we evaluated the effects of a maternal high-fat diet (HFD) during lactation on the development of tauopathy in the THY-Tau22 mouse strain, a model of progressive tau pathology associated with cognitive decline. During lactation, dams were fed either a chow diet (13.6% of fat) or a HFD (58% of fat). At weaning, offspring was fed a chow diet until sacrifice at 4 months of age (the onset of tau pathology) or 7 months of age (the onset of cognitive impairment). During lactation, maternal HFD increased body weight gain in offspring. At 3 months of age, maternal HFD led to a mild glucose intolerance only in male offspring. Moreover, it impaired spatial memory in both male and female 6-month-old offspring, with males being more impacted. These cognitive deficits were associated with increased phosphorylation of hippocampal tau protein-observed at 4 months in males and at 7 months in females, highlighting a sex-specific temporal shift. Additionally, maternal HFD modified adult hippocampal neurogenesis (AHN), leading to an increase of mature neuronal cells number in females and of dendritic arborization length in males. Synaptic analysis further revealed that maternal HFD led to synaptic loss only in males. Finally, multi-omics approaches showed that maternal HFD has long-term consequences on both transcriptome, proteome and regulome, this effect being also sex-dependent with mitochondrial pathways, ribosomal activity, cilium and the extracellular matrix predominantly impacted in males, while gliogenesis, myelination and synaptic plasticity were primarily affected in females. Regulome analysis suggested that this sex-dependent phenotype was more related to a temporal shift rather than distinct sex-specific alterations. Collectively, our data suggest that maternal malnutrition accelerates the development of tauopathy in THY-Tau22 offspring, with sex-dependent effects, males being impacted earlier than females. These findings highlight the critical role of the perinatal environment as a key window of opportunity for interventions aimed at preventing the development of neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Reduced levels of synaptic vesicle protein 2A in the extracellular vesicles and brain of Alzheimer's disease- associations with Aβ, tau and synaptophysin

BackgroundSynaptic dysfunction plays an important role in Alzheimers disease (AD) and is an emerging imaging and fluid biomarker. Here, we aimed to assess the regional expression of synaptic vesicle glycoprotein 2A (SV2A) in the brain and extracellular vesicles of AD patients and its associations with the APOE {varepsilon}4 allele, amyloid-{beta}, tau pathologies, and other synaptic markers. MethodsMass spectrometry-based synaptosome proteomics was performed on brain-derived extracellular vesicles (BdEVs) isolated from the frontal cortex of 17 AD patients and 4 NCs. Immunohistochemical staining for SV2A, synaptophysin, amyloid-{beta} and phospho-tau was performed on postmortem tissue from the frontal, temporal, and entorhinal cortices and hippocampus of 40 AD patients and 44 nondemented controls (NCs). ResultsReduced levels of synaptic proteins, including synaptotagamin, GAP43, SYT1, SNAP25 and 14-3-3{zeta}, were positively correlated with SV2A and negatively correlated with GFAP and NEFL in BdEVs from AD patients and NCs. We detected lower levels of SV2A in the hippocampus and entorhinal cortex of AD compard to NCs, and in APOE {varepsilon}4 carriers than in noncarriers. SV2A levels were positively correlated with synaptophysin and negatively correlated with the levels of the amyloid-{beta}, phospho-tau, and Braak stages. ConclusionsThis study provides postmortem evidence of synaptic markers and reduced regional levels of SV2A in brain tissue slices and BdEVs from AD patients compared with NCs and in APOE {varepsilon}4 carriers compared to non-carriers. SV2A could serve as a valuable marker for monitoring synaptic degeneration in AD.

neuroscience↗

bioRxiv2025

Astrocyte and mitochondrial footprints in brain-derived extracellular vesicles predict tau pathology

Tauopathies are neurodegenerative disorders characterized by abnormal tau aggregation, with primary 3R (e.g., Picks disease, PiD) and 4R (e.g., progressive supranuclear palsy, PSP) variants posing a significant diagnostic challenge. Here, we examined brain-derived extracellular vesicles (BD-EVs) isolated from the prefrontal cortex of PiD (3R), PSP (4R), and non-demented controls (CTRL) to determine if these vesicles reflect disease-specific proteomic signatures. We found that while tau pathology does not substantially alter BD-EV concentration or the enrichment of core vesicular markers, it does influence their size distribution and protein cargo. BD-EV samples from PiD patients exhibited a greater abundance of small vesicles and distinct protein profiles when compared to PSP and CTRL. Weighted Gene Co-expression Network Analysis (WGCNA) identified four key protein modules to account for variance between patient groups Endoplasmic Reticulum, Mitochondria, Microtubules, and Trivalent Inorganic Cation Transport. In PiD, astrocyte-derived mitochondrial proteins were significantly elevated, whereas neuronal microtubule-related proteins were diminished relative to both PSP and CTRL. Notably, changes in the mitochondrion and microtubule modules enhanced the detection of PiD pathology. Cellular origin annotation revealed a marked shift in BD-EV composition: PiD samples exhibited an increased astrocytic signature, while both PiD and PSP showed a reduction in neuronal proteins compared to CTRL. Crucially, the enrichment of astrocytic mitochondrial and endoplasmic reticulum proteins, alongside reduced neuronal proteins, correlated strongly with the severity of tau pathology (AT8-stained aggregates) in patient brains. These findings demonstrate that BD-EVs capture tau isoform-specific cellular and molecular alterations, offering a window into disease mechanisms at the neuron-glia interface. By linking distinct protein signatures and their cellular origins to tau pathology severity, our results highlight the potential of BD-EV profiling as a biomarker strategy for distinguishing between and monitoring the progression of 3R and 4R tauopathies.

neuroscience↗

bioRxiv2024

Hampered AMPK-ULK1 cascade in Alzheimer disease (AD) instigates mitochondria dysfunctions and AD-related alterations that are alleviated by metformin

BackgroundMitochondrial structure and function alterations are key pathological features in Alzheimers disease (AD) brains. The adenosine monophosphate-activated protein kinase (AMPK) and its downstream effector Unc-51 like autophagy activating kinase 1 (ULK1) represent a key node controlling mitochondria health, the alteration of which likely contribute to AD development. MethodsWe designed this study to investigate AMPK-ULK1 activation state in post-mortem human sporadic AD brains, in 3xTgAD mice that recapitulate most of human AD features, and in neuronal cells expressing the amyloid precursor protein with the familial Swedish mutation (APPswe). We examined the impact of the pharmacological and genetic modulation of AMPK-ULK1 cascade on mitochondria structure and functions in APPswe cells. We evaluated the potential beneficial impact of AMPK-ULK1 activation by Metformin (Met) on mitochondria defects, as well as on early- and late-stage AD-related alterations in vivo and ex vivo. ResultsAt first, we show that AMPK-ULK1 cascade is defective in murine and human AD brains as well as in APPswe cells. We then report that Met administration to 3xTgAD mice alleviates the alterations of neuronal mitochondria structure and function and we consolidate these results in cells using both pharmacological and genetic tools to modulate AMPK-ULK1 cascade. In mice brains, Met reduces the early accumulation of APP C-terminal fragments (APP-CTFs) as well as the amyloid beta (A{beta}) burden present in aged mice. Mechanistically, we show that Met increases the localization of APP-CTFs within cathepsin D-positive lysosomal compartments in vivo and enhances cathepsin D activity in vitro. The reduction of A{beta} load by Met occurs through an increased recruitment of Iba1+ cells to A{beta} plaques and an enhancement of the phagocytic activity of microglia. Accordingly, in symptomatic 3xTgAD mice, Met alleviates microgliosis and astrogliosis, modulates microglia morphology, reduces peripheral proinflammatory cytokines levels, and regulates the expression of a set of inflammatory genes. In addition, Met normalizes dendritic spines shape in organotypic hippocampal slice cultures modeling AD and improves learning performance of 3xTgAD mice. ConclusionsOur study demonstrates potential therapeutic benefits of targeting AMPK-ULK1 cascade to reverse both early and late AD-related alterations, deserving further investigation in fundamental research and in human clinical studies.

neuroscience↗

bioRxiv2023

A Small Tau Fragment Specifically Templates Four Repeat Tau Aggregates Through Multiple Generations

Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau, folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high {beta}- sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting {beta}-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19- residue peptide. These peptide fibrils function as partial prions to recruit naive 4R tau--ten times the length of the peptide--and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform-specific therapeutic interventions. Significance StatementA structural motif corresponding to a short junction sequence spanning R2 and R3 forms fibrils that adopt a fold characteristic of 4R tauopathy fibrils and induces misfolding of the larger tau protein with loss of microtubule binding and a prion-like specificity for 4R tau. Simulations, validated experimentally, pinpointed the specific amino acids in the peptide that can toggle its properties between aggregation competent and incompetent. The modifications suggest design principles for a therapeutic intervention potentially capable of disaggregating tau or preventing its aggregation in the 4R tauopathies.

molecular biology↗

bioRxiv2023

Strategy of selection and optimization of single domain antibodies targeting the PHF6 linear peptide within the Tau intrinsically disordered protein

The use of VHHs (Variable domain of the Heavy-chain of the Heavy-chain-only antibodies) as disease-modifying biomolecules in neurodegenerative disorders holds promises including to target aggregation-sensitive proteins. Exploitation of their clinical values dependents however on the capacity to deliver VHHs with optimal physico-chemical properties for their specific context of use. We described previously a VHH with high therapeutic potential in a family of neurodegenerative diseases called tauopathies. The activity of this promising parent VHH named Z70 relies on its binding within the central region of the Tau protein. Accordingly, we carried out random mutagenesis followed by yeast two-hybrid screening to obtain optimized variants. The VHHs selected from this initial screen targeted the same epitope as VHH Z70 as shown using nuclear magnetic resonance spectroscopy and had indeed improved binding affinities according to dissociation constant values obtained by surface plasmon resonance spectroscopy. The improved affinities can be partially rationalized based on three-dimensional structures of three complexes consisting of an optimized VHH and a peptide containing the Tau epitope. Interestingly, the ability of the VHH variants to inhibit Tau aggregation and seeding could not be predicted from their affinity alone. We indeed showed that the in vitro and in cellulo VHH stabilities are other limiting key factors to their efficacy. Our results demonstrate that only a complete pipeline of experiments, here described, permits a rational selection of optimized VHH variants, resulting in our capacity to propose two VHH variants derived from the parent Z70 for their next development steps.

biochemistry↗

bioRxiv2023

Accumulation of Tau in Extracellular Vesicles Disturbs the Astrocytic Mitochondrial System

Tauopathies are neurodegenerative disorders involving the accumulation of tau isoforms in cell subpopulations such as astrocytes. The origins of the 3R and 4R isoforms of tau that accumulate in astrocytes remain unclear. Extracellular vesicles (EVs) were isolated from primary neurons overexpressing 1N3R or 1N4R tau or from human brain extracts (progressive supranuclear palsy or Pick disease patients or controls) and characterized (electron microscopy, nanoparticle tracking analysis (NTA), proteomics). After the isolated EVs were added to primary astrocytes or human iPSC-derived astrocytes, tau transfer and mitochondrial system function were evaluated (ELISA, immunofluorescence, MitoTracker staining). We demonstrated that neurons in which 3R or 4R tau accumulated had the capacity to transfer tau to astrocytes and that EVs were essential for the propagation of both isoforms of tau. Treatment with tau-containing EVs disrupted the astrocytic mitochondrial system, altering mitochondrial morphology, dynamics and redox state. Although similar levels of 3R and 4R tau were transferred, 3R tau-containing EVs were significantly more damaging to astrocytes than 4R tau-containing EVs. Moreover, EVs isolated from the brain fluid of patients with different tauopathies affected mitochondrial function in astrocytes derived from human iPSCs. Our data highlight that tau pathology spreads to surrounding astrocytes via EVs-mediated transfer and modify their function.

neuroscience↗

bioRxiv2021

Alzheimer's brain inoculation in Aβ-plaque bearing mice: synaptic loss is linked to tau seeding and low microglial activity

Alzheimers disease (AD) is characterized by intracerebral accumulations of extracellular amyloid-{beta} (A{beta}) plaques and intracellular tau pathology that spread in the brain. Tau lesions occur in the form of neuropil threads, neurofibrillary tangles, and neuritic plaques i.e. tau aggregates within neurites surrounding A{beta} deposits. The cascade of events linking these lesions and synaptic or memory impairments are still debated. Intracerebral infusion of human AD brain extracts in A{beta} plaque-bearing mice that do not overexpress pathological tau proteins induces tau pathologies following heterotopic seeding of mouse tau protein. There is however little information regarding the downstream events including synaptic or cognitive repercussions of tau pathology induction in these models. In the current study, human AD brain extracts (ADbe) and control-brain extracts (Ctrlbe) were infused in the hippocampus of A{beta} plaque-bearing APPswe/PS1dE9 mice. Memory, synaptic density, as well as A{beta} plaque and tau aggregate loads, microgliosis, astrogliosis at the inoculation site and in connected regions (perirhinal/entorhinal cortex) were evaluated 4 and 8 months post-inoculation. ADbe inoculation induced memory deficit. It increased deposition of A{beta} plaques close to the inoculation site. Tau pathology was also induced in ADbe-inoculated mice. Neuropil threads and neurofibrillary tangles occurred next to the inoculation site and spread to connected regions notably the perirhinal/entorhinal cortex. Neuritic plaque pathology was detected in both ADbe- and Ctrlbe- inoculated animals but ADbe inoculation increased the severity close and at distance of the inoculation site. Finally, ADbe inoculation reduced synaptic density close to the inoculation site and in connected regions as the perirhinal/entorhinal cortex. Synaptic impairments were correlated with increased severity of neuritic plaques but not of other tau lesions or A{beta} lesions, which suggests that neuritic plaques are a culprit for synaptic loss. Synaptic density was also associated with microglial load. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/438654v4_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@791f29org.highwire.dtl.DTLVardef@1ecf87corg.highwire.dtl.DTLVardef@adb3a0org.highwire.dtl.DTLVardef@1ebef93_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

A β-secretase modulator decreases Tau pathology and preserves short-term memory in a mouse model of neurofibrillary degeneration

A structure-activity relationship has enabled us to identify two molecules, MAGS02-14 and PEL24-199, sharing a {beta}-secretase modulatory effect but having or not a lysosomotropic activity, respectively. More importantly, MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom. However, which of the lysosomotropic and/or {beta}-secretase modulating activities is necessary for the pharmacological effect in vivo remains ill-defined. To address this question, the THY-Tau22 transgenic model of NFD was treated for 6 weeks in a curative paradigm and short-term memory, Tau burden, and inflammatory processes were studied. PEL24-199, possessing only the {beta}-secretase modulatory activity, was shown to restore the short-term memory and to reduce NFD. This effect was associated with reduced phosphorylation of Tau, increased phosphatase expression, and a decrease of astrogliosis. Our results therefore suggest that the lysosomotropic activity may be dispensable for the effect on both A{beta} and Tau pathologies.

pharmacology and toxicology↗

bioRxiv2020

A novel equilibrative nucleoside transporter 1 inhibitor alleviates Tau-mediated neurodegeneration

Tau hyperphosphorylation favors the formation of neurofibrillary tangles and triggers the gradual loss of neuronal functions in tauopathies, including Alzheimers disease. Herein, we demonstrated that chronic treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1), which plays a critical role in controlling adenosine homeostasis and purine metabolism in the brain, exerted beneficial effects in a mouse model of tauopathy (Thy-Tau22, Tau22). Chronic treatment with J4 improved spatial memory deficits, mitochondrial dysfunction, synaptic plasticity impairment, and gliosis. Immunofluorescence assays showed that J4 not only reduced Tau hyperphosphorylation but also normalized the reduction in mitochondrial mass and suppressed the abnormal activation of AMP-activated protein kinase (AMPK), a pathogenic feature that is also observed in the brains of patients with tauopathies. Given that AMPK is an important energy sensor, our findings suggest that energy dysfunction is associated with tauopathy and that J4 may exert its protective effect by improving energy homeostasis. Bulk RNA-seq analysis revealed that J4 also mitigated immune signature associated with Tau pathology including C1q upregulation and A1 astrocyte markers. Collectively, our findings suggest that identifying strategies for normalizing energy and neuroimmune dysfunctions in tauopathies through adenosinergic signaling modulation may pave the way for the development of treatments for Alzheimers disease.

neuroscience↗

bioRxiv2020

Role of TNF-α among inflammatory molecules secreted by injured astrocytes in the modulation of in vitro neuronal networks

Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide. Despite its high prevalence and extensive efforts to develop neuroprotective therapies, effective treatments for TBI are still limited. Among important neuronal damages, TBI induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. Injured astrocytes respond in diverse mechanisms that result in reactive astrogliosis and are involved in the physiopathological mechanisms of TBI in an extensive and sophisticated manner. The establishment of effective neuroprotective treatments for TBI requires to better understand the complex biochemical interactions between activated astrocytes and neurons that contribute to the secondary injury. To address this challenge, we studied in vitro the role of mechanically injured astrocytes on the growth and synaptic connections of cortical neuronal networks of controlled architectures grown on well-defined protein micropatterns. Astrocytes were cultivated on elastic membranes and mechanically activated by stretching cycles. The culture media of healthy or activated astrocytes was then introduced on neuronal networks. We analyzed the neuronal viability, the neurite growth and the synaptic density of neuronal networks to understand the role of the inflammatory molecules secreted by mechanically activated astrocytes. Furthermore, we cultivated neuronal networks during 13 days with different doses of TNF- in order to decipher its individual contribution among the other cytokines. Here we show that the ratio of tubulin to synapsin area was significantly higher in neuronal networks treated with either 4 or 2 doses of TNF-, suggesting that TNF- can promote the tubulin polymerization process. Assuming that TNF- can bind to either TNFR1 or TNFR2 receptors, which lead respectively to the cell survival or the cell apoptosis, we studied the modulation of the both TNF- receptors in response to the medium of mechanically activated astrocytes and different doses of TNF-. Our findings indicate that the amount of both receptors increases with the maturation of the network. In addition, we observed a significant modulation of the amount of TNFR1 and TNFR2 in response to the media of injured astrocytes that leads to a large imbalance between both receptors, suggesting an important role for TNF-signaling in the physiopathological mechanisms of TBI.

biophysics↗

bioRxiv2019

Caffeine consumption during pregnancy accelerates the development of cognitive deficits in offspring in a model of tauopathy

Psychoactive drugs used during pregnancy can affect the development of the brain of offspring, directly triggering neurological disorders or increasing the risk for their occurrence. Caffeine is the most widely consumed psychoactive drug, including during pregnancy. In Wild type mice, early life exposure to caffeine renders offspring more susceptible to seizures. Here, we tested the long-term consequences of early life exposure to caffeine in THY-Tau22 transgenic mice, a model of Alzheimers disease-like Tau pathology. Caffeine exposed mutant offspring developed cognitive earlier than water treated mutants. Electrophysiological recordings of hippocampal CA1 pyramidal cells in vitro revealed that early life exposure to caffeine changed the way the glutamatergic and GABAergic drives were modified by the Tau pathology. We conclude that early-life exposure to caffeine affects the Tau phenotype and we suggest that caffeine exposure during pregnancy may constitute a risk-factor for early onset of Alzheimers disease-like pathology.

neuroscience↗

bioRxiv2018

Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology

BackgroundThousands of SNPs associated with risk of Alzheimers disease (AD) in genome-wide association studies (GWAS) do not reach genome-wide significance. When combined, they contribute however to a highly predictive polygenic risk score. The relevance of these subthreshold risk genes to disease, and how their combined predictive power translates into functionally relevant disease pathways, is unknown. We investigate here at the genome-wide level and in an unbiased way to what extent AD risk genes show altered gene expression in the context of increasing A{beta} or Tau pathology in mouse models of AD.\n\nMethodsWe used an existing GWAS data set to generate lists of candidate AD genes at different levels of significance. We performed transcriptomic analysis on wild-type and transgenic APP/PS1 (APPtg) and Thy-TAU22 (TAUtg) mouse models at early and late stage of disease. We used unbiased weighted gene co-expression network analysis (WGCNA) to identify clusters of co-regulated genes responsive to A{beta} or TAU pathology. Gene set enrichment was used to identify clusters that were enriched for AD risk genes.\n\nFindingsConsistent and significant enrichment of AD risk genes was found in only one out of 63 coexpression modules. This module is highly responsive to A{beta} but not to TAU pathology. We identify in this module 18 AD risk genes (p-value=6{middle dot}5e-11) including 11 new ones, GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN and BLNK. All are expressed in microglia, have a binding site for the transcription factor SPI1 (PU.1), and become significantly upregulated when exposed to A{beta}. A subset regulates FC-gamma receptor mediated phagocytosis.\n\nInterpretationGenetic risk of AD is functionally translated into a microglia pathway responsive to A{beta} pathology. This insight integrates aspects of the amyloid hypothesis with genetic risk associated to sporadic AD.

neuroscience↗

bioRxiv2018

AMP-activated protein kinase is essential for the maintenance of energy levels during synaptic activation

While accounting for 2% of the total body mass, the brain is the organ that consumes the most energy. Although it is widely acknowledged that neuronal energy metabolism is tightly regulated, the mechanism how neurons meet their energy demand to sustain synaptic transmission remains poorly studied. Here we provide substantial evidence that the AMP-activated protein kinase (AMPK) plays a leading role in this process. Our results show that following synaptic activation, AMPK activation is required to sustain neuronal energy levels particularly through mitochondrial respiration. Further, our studies revealed that this metabolic plasticity regulated by AMPK is required for the expression of immediate early genes, synaptic plasticity and memory formation. These findings are important in the context of neurodegenerative disorders, as AMPK deregulation as it is observed in Alzheimers disease, impairs the metabolic response to synaptic activation. Altogether, our data provides the proof of concept that AMPK is an essential player in the regulation of neuroenergetic metabolism plasticity induced in response to synaptic activation.

neuroscience↗

bioRxiv2018

Contribution of the endosomal-lysosomal and proteasomal systems in Amyloid-β Precursor Protein derived fragments processing

A{beta} peptides, the major components of amyloid deposits of Alzheimers disease, are released following sequential cleavages by secretases of its precursor named the amyloid precursor protein (APP). In addition to secretases, degradation pathways, in particular the endosomal/lysosomal and proteasomal systems have also been reported to contribute to APP processing. However, the respective role of each of these pathways towards APP metabolism remains to be established. To address this, we used HEK 293 cells and primary neurons expressing full-length APPWT or the {beta}-secretase-derived C99 fragments ({beta}-CTFs) in which degradation pathways were selectively blocked using pharmacological drugs. APP metabolites, including carboxy-terminal fragments (CTFs), soluble APP (sAPP) and A{beta} peptides were studied. In this report, we show that APP-CTFs produced from endogenous or overexpressed full-length APP are mainly processed by {gamma}-secretase and the endosomal/lysosomal pathway, while in sharp contrast, overexpressed C99 alone is mainly degraded by the proteasome and to a lesser extent by {gamma}-secretase.

neuroscience↗