Biology subjects

Xu, J.

Publications and source records attributed to Xu, J..

At least 541 records · Page 30Linked to original sources

bioRxiv2022

Zbtb14 regulates monocyte and macrophage development through inhibiting pu.1 expression in zebrafish

Macrophages and their precursor cells, monocytes, are the first line of defense of the body against foreign pathogens and tissue damage. Although the origins of macrophages are diverse, some common transcription factors (such as PU.1) are required to ensure proper development of monocytes/macrophages. Here we report that the deficiency of zbtb14, a transcription repressor gene belonging to ZBTB family, leads to an aberrant expansion of monocyte/macrophage population in zebrafish. Mechanistically, Zbtb14 functions as a negative regulator of pu.1, and SUMOylation on a conserved lysine is essential for the repression activity of Zbtb14. Moreover, a serine to phenylalanine mutation found in an acute myeloid leukemia (AML) patient could target ZBTB14 protein to autophagic degradation. Hence, ZBTB14 is a newly identified gene implicated in both normal and malignant myelopoiesis.

developmental biology↗

bioRxiv2022

Optimal transport analysis of single-cell transcriptomics directs hypotheses prioritization and validation

The explosive growth of regulatory hypotheses from single-cell datasets demands accurate prioritization of hypotheses for in vivo validation. However, current computational methods emphasize overall accuracy in regulatory network reconstruction rather than prioritizing a limited set of causal transcription factors (TFs) that can be feasibly tested. We developed Haystack, a hybrid computational-biological algorithm that combines active learning and the concept of optimal transport theory to nominate and validate high-confidence causal hypotheses. Our novel approach efficiently identifies and prioritizes transient but causally-active TFs in cell lineages. We applied Haystack to single-cell observations, guiding efficient and cost-effective in vivo validations that reveal causal mechanisms of cell differentiation in Drosophila gut and blood lineages. Notably, all the TFs shortlisted for the final, imaging-based assays were validated as drivers of differentiation. Haystacks hypothesis-prioritization approach will be crucial for validating concrete discoveries from the increasingly vast collection of low-confidence hypotheses from single-cell transcriptomics.

bioinformatics↗

bioRxiv2022

Epo-IGF1R crosstalk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm

We find that in regenerative erythropoiesis, the erythroid progenitor landscape is reshaped, and a previously undescribed progenitor population with CFU-E activity (stress CFU-E/sCFU-E) is markedly expanded to restore the erythron. sCFU-E are targets of erythropoietin (Epo) and sCFU-E expansion requires signaling from the Epo receptor (EpoR) cytoplasmic tyrosines. Molecularly, Epo promotes sCFU-E expansion via JAK2/STAT5-dependent expression of IRS2, thus engaging the pro-growth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R/IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR lacking cytoplasmic tyrosines. This sCFU-E pathway is the major pathway involved in erythrocytosis driven by the oncogenic JAK2 mutant, JAK2(V617F), in myeloproliferative neoplasm. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis. In myeloproliferative neoplasm patient samples, the number of sCFU-E like cells increases, and inhibition of IGR1R/IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. In summary, we identify a new stress-specific erythroid progenitor cell population that links regenerative erythropoiesis to pathogenic erythrocytosis. Key PointsO_LIEpo-induced IRS2 allows engagement of IGF1R signaling to expand a previously unrecognized progenitor population in erythropoietic stress. C_LIO_LITruncated EpoR does not support stress CFU-E expansion and protects against JAK2(V617F)-driven erythrocytosis in MPN. C_LI

developmental biology↗

bioRxiv2022

Underlying beneficial effects of Rhubarb on constipation-induced inflammation, disorder of gut microbiome and metabolism

BackgroundAlthough constipation is a common syndrome and a worldwide health problem. Constipation patients are becoming younger with a 29.6% overall prevalence in the children, which has captured great attention because of its epigenetic rejuvenation and recurrent episodes. Despite the usage of rhubarb to relieve constipation, novel targets and genes involved in target-relevant pathways with remarkable functionalities should still be sought after. Materials and methodsWe established a reliable constipation model in C57B/6N male mice using intragastric administration diphenoxylate and the eligible subjects received 600mg/25g rhubarb extraction to ameliorate constipation. Resultant constipation was morphological and genetically compared with the specimen from different groups. ResultsThe constipation mice exhibited thicker muscle layers, improved content of cytokines, including IL-17 and IL-23, and lower content of IL-22. The bacterial abundance and diversity varied tremendously. Notably, the alterations were reversed after rhubarb treatment. Additionally, SCFA and MLCFA were significantly influenced by constipation accompanied by enhanced expressions of SCFA receptors, GPR41 and GPR43. ConclusionThis thesis has provided an insight that rhubarb promoted the flexibility of collagen fiber, reduced pro-inflammatory cytokines and enhanced anti-inflammatory cytokines, and maintained intestinal microflora balance with potential effects on affecting the metabolism of fatty acids and polyamines.

pharmacology and toxicology↗

bioRxiv2022

Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3

Enteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this diverse genus of viruses. We have previously identified the actin histidine methyltransferase SETD3 as a critical host factor physically interacting with the viral protease 2A. Here, we report the 3.5 [A] cryo-EM structure of SETD3 interacting with coxsackievirus B3 2A at two distinct interfaces, including the substrate-binding surface within the SET domain. Structure-function analysis revealed that mutations of key residues in the SET domain resulted in severely reduced binding to 2A and complete protection from enteroviral infection. Our findings provide insight into the molecular basis of the SETD3-2A interaction and a framework for the rational design of host-directed therapeutics against enteroviruses.

biophysics↗

bioRxiv2022

A two-step in vivo CRISPR screen unveils pervasive RNA binding protein dependencies for leukemic stem cells and identifies ELAVL1 as a therapeutic target

Acute myeloid leukemia (AML) progression and relapse is fueled by self-renewing leukemic stem cells (LSCs) whose molecular determinants have been difficult to discern from normal hematopoietic stem cells (HSCs) or to uncover in screening approaches focused on general AML cell properties. We have identified a unique set of RNA binding proteins (RBPs) that are enriched in human AML LSCs but repressed in HSCs. Using an in vivo two step CRISPR-Cas9-mediated screening approach to specifically score for cancer stem cell functionality, we found 32 RBPs essential for LSC propagation and self-renewal in MLL-AF9 translocated AML. Using knockdown or small molecule approaches we show that targeting key hit RBP ELAVL1 impaired LSC-driven in vivo leukemic reconstitution and selectively depleted primitive AML cells vs. normal hematopoietic stem and progenitors. Importantly, knockdown of Elavl1 spared HSCs while significantly reducing LSC numbers across genetically diverse leukemias. Integrative RNA-seq and eCLIP-seq profiling revealed hematopoietic differentiation, RNA splicing and mitochondrial metabolism as key features defining the leukemic ELAVL1-mRNA interactome with the mitochondrial import protein TOMM34 being a direct ELAVL1-stabilized target whose inhibition impairs AML propagation. Altogether, through the use of a stem cell-adapted in vivo CRISPR dropout screening strategy, this work demonstrates that a wide variety of post-transcriptionally acting RBPs are important regulators of LSC-survival and self-renewal and, as exemplified by ELAVL1, highlights their potential as therapeutic targets in AML.

cancer biology↗

bioRxiv2022

An Igh novel enhancer modulates antigen receptor diversity by determining locus conformation

The Igh locus is organized into a developmentally regulated topologically associated domain (TAD) that is divided into subTADs. Here we identify a series of novel enhancers (NEs) that collaborate to configure the locus, determine transcriptional potential in over a hundred functional VH genes and their usage in V(D)J recombination. NE1 engages in a network of long-range interactions that interconnect the subTADs and the recombination center at the DHJH gene cluster. Deletion of NE1 alters discrete chromatin loops, higher order locus conformation, locus-wide VH gene transcription and regional V gene utilization that is linked to a greatly reduced splenic B1 B cell compartment. NE1 blocks long-range loop extrusion that in turn contributes to locus contraction and determines the proximity of distant VH genes to the recombination center. NE1 is a critical architectural element that coordinates chromatin conformational states that favor VH gene transcription or V(D)J rearrangement.

immunology↗

bioRxiv2022

In situ architecture and membrane fusion of SARS-CoV-2 Delta variant

Among the current five Variants of Concern, infections caused by the SARS-CoV-2 B.1.617.2 (Delta) variant are often associated with the greatest severity. Despite recent advances on the molecular basis of elevated pathogenicity using recombinant proteins, architecture of intact Delta virions remains veiled. Moreover, molecular evidences for the detailed mechanism of S-mediated membrane fusion are missing. Here we reported the in situ structure and distribution of S on the authentic Delta variant, and discovered invagination in the distinctive Delta architecture. We also captured fusion snapshots from the virus-virus fusion events, provided structural evidences for Deltas attenuated dependency on cellular factors for fusion activation, and proposed a model of S-mediated membrane fusion. Site-specific glycan analysis revealed increased oligomannose-type glycosylation of native Delta S over that of the Wuhan-Hu-1 S. Together, these results disclose distinctive factors of Delta being the most virulent SARS-CoV-2 variant. In BriefCryo-ET of intact SARS-CoV-2 Delta variant revealed its distinctive architecture and captured snapshots of its membrane fusion in action.

biophysics↗

bioRxiv2022

Resetting of H3K4me2 during mammalian parental-to-zygote transition

Upon sperm and oocyte fertilization, the embryo undergoes drastic histone modification reprogramming during pre-implantation development. In this study, we investigated the erasure and re-establishment of H3K4me2 in mouse GV, MII, and embryos using an improved approach called Cleavage Under Targets and Release Using Nuclease (CUT&RUN) with high-throughput sequencing. We found that H3K4me2 extensively occurs as a non-canonical pattern in mouse GV oocytes and early embryos, and parental H3K4me2 was erased by maternal LSD2 during forming the pronucleus in the zygote. The H3K4me2 was erased from GV to MII oocyte and was re-established in the late two-cell stage, removing this epigenetic burden is crucial for ZGA. We then revealed the H3K4me2 locates widespread in the CpG-rich and hypomethylated regulatory regions in the four-cell stage, and the eight-cell stage, but dramatic changes occurred in the inner cell mass (ICM) in mouse embryos. Then, these CpG-rich H3K4me2 regulatory regions became either activated or repressed. To summarize, in this study, we elucidated the pattern of H3K4me2 transition from parent to zygote and H3K4me2 profile during early embryo development. Our findings might provide deeper insights into epigenetic reprogramming during early development and in vitro fertilization in mammalian. HighlightsO_LIH3K4me2 showed differential patterns in sperms and oocytes; non-canonical pattern occurred in GV oocytes, but canonical patterns were found in the sperm cells of mice. C_LIO_LIThe H3K4me2 peaks of GV were almost erased in MII oocytes and reconstructed after the major ZGA occurred. Maternal LSD2 was found to regulate H3K4me2 resetting during the parental-to-zygote transition. H3K4me2 may impose an "Epigenetic Burden" on ZGA. C_LIO_LINon-canonical H3K4me2 pattern was found in mammalian embryos, however, pervasive H3K4me2 in CpG-rich regulatory regions were found in four-cell and eight-cell stage embryos; The CpG-rich H3K4me2 regulatory regions were either activated or repressed in the ICM. C_LI

genetics↗

bioRxiv2022

The radio-protective effects of (-)-Epigallocatechin-3-gallate (EGCG): regulating macrophage function in radiation-induced intestinal injury.

Accidental and medical radiation exposure may cause radiation-induced intestinal injury (RIII), a catastrophic disease requiring efficient therapies. (-)-Epigallocatechin-3-gallate (EGCG), a major constituent of green tea, has been shown to have potent biological activity as well as strong anti-inflammation effects. Here, we demonstrate that EGCG treatment not only protects mice against total body irradiation (TBI)-induced toxicity and weight loss but also alleviates whole abdominal irradiation (WAI)-induced intestinal injury. EGCG promotes proliferation and survival of intestinal stem cells, inhibits radiation-induced apoptosis and inflammation. At the same time, EGCG preserves the composition of the gut microbiota in WAI mice. In vitro, we demonstrate that EGCG regulates the release of radiation-induced inflammatory factors by inhibiting inflammatory pathways such as toll-like receptor signaling pathway in peritoneal macrophages. Mechanistically, the radioprotective effect of EGCG was likely attributable to its preservation on macrophages and the colonized gut microbiota composition, thus relieving the intestinal inflammation. EGCG provides a novel strategy to mitigate RIII and improve the prognosis of patients after radiotherapy.

cell biology↗

bioRxiv2022

Sugar transporter Slc37a2 regulates bone metabolism via a dynamic tubular lysosomal network in osteoclasts

Osteoclasts are giant bone-digesting cells that harbour specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclasts resorptive apparatus. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. We demonstrate that Slc37a2 localizes to the SL limiting membrane and that these organelles adopt a hitherto unnoticed but dynamic tubular network in living osteoclasts that is required for bone digestion. Accordingly, mice lacking Slc37a2 accrue high bone mass owing to uncoupled bone metabolism and disturbances in SL export of monosaccharide sugars, a prerequisite for SL delivery to the ruffled border. Thus, Slc37a2 is a physiological component of the osteoclasts unique secretory organelle and a potential therapeutic target for metabolic bone diseases.

cell biology↗

bioRxiv2022

HSP90.6 is involved in grain filling via carbon and nitrogen metabolism in maize.

Carbon and nitrogen are the two most abundant nutrients in all living things, and their metabolism maintains normal plant growth. However, the molecular mechanism underlying carbon and nitrogen metabolism remains largely unknown. Here, we found that HSP90.6 is involved in the metabolism of carbon and nitrogen. We performed gene cloning and functional characterization of a maize EMS mutant ehsp90.6, whose kernels were small. HSP90.6 encodes heat shock protein 90.6, which has a single-amino acid mutation within its HATPase_c domain. Transcriptome profiling showed that the expression of amino acid biosynthesis- and carbon metabolism-related genes was significantly downregulated in hsp90.6. HSP90.6 is involved in the 26S proteasome degradation pathway, which affects nitrogen recycling to regulate amino acid synthesis; this occurs by interactions between HSP90.6 and the 26S proteasome subunits RPN6 and PBD2 (PRC2). The loss of HSP90.6 significantly reduced the activity of the 26S proteasome, resulting in the accumulation of ubiquitinated proteins and defects in nitrogen recycling. Moreover, HSP90.6 interacted with the 14-3-3 protein GF14-6 to participate in carbon metabolism. Together, these findings revealed that HSP90.6 regulates nutrient metabolism in maize seeds by affecting 26S proteasome-mediated nitrogen recycling and GF14-6-mediated carbon metabolism. One sentence summaryHSP90.6 is involved in nutrient metabolism via 26S proteasome-mediated protein degradation to promote nitrogen recycling and GF14-6 protein-mediated carbon metabolism. The author responsible for the distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (https://academic.oup.com/plcell/pages/General-Instructions) is Weibin Song (songwb@cau.edu.cn). HighlightsO_LIHATPase_c is necessary for HSP90.6 to regulate maize kernel development. C_LIO_LIHSP90.6 is involved in nitrogen recycling via the 26S proteasome degradation pathway. C_LIO_LIHSP90.6 interacts with the 14-3-3 protein GF14-6 to affect carbon metabolism. C_LI IN A NUTSHELLO_ST_ABSBackgroundC_ST_ABSSeeds are the main harvested organs of maize. Understanding the regulatory mechanism of grain filling is helpful to cultivate high-quality and high-yield maize. In the past few years, the regulatory network of grain filling has been explored through multiple means, including transcriptomic, proteomic and functional genomic techniques. Many genes that control grain filling through different mechanisms have been cloned, such as CTLP1 (Choline Transporter-like Protein 1), OS1 (Opaque Endosperm and Small Germ 1), and MN6 (Miniature Seed6). To identify new genes involved in maize grain filling, ethyl methanesulfonate (EMS) was used to induce mutations, and the ehsp90.6 mutant, which exhibited abnormal kernel development, was isolated by bulked segregant analysis RNA sequencing (BSR). QuestionWhy does the single-amino acid mutation of HSP90.6 affect grain size, and how does the loss of HSP90.6 affect grain filling? FindingsA single-amino acid mutant (ehsp90.6) and knockout mutant (hsp90.6) were obtained. We found that HSP90-6 was involved in the regulation of maize grain filling. A single-single amino acid mutation in the HATPase_c domain reduced the ATPase activity of HSP90.6, resulting in smaller grains. The functional loss of HSP90.6 resulted in the expression of amino acid biosynthesis- and carbon metabolism-related genes being significantly downregulated in hsp90.6. We indicated that HSP90.6 is involved in the 26S proteasome degradation pathway, which affects nitrogen recycling to regulate amino acid synthesis by interacting with the 26S proteasome subunits RPN6 and PBD2 (PRC2). Moreover, HSP90.6 was found to interact with the 14-3-3 protein GF14-6 to participate in carbon metabolism. Next stepsTo further verify that the interaction between HSP90.6 and 26S proteasome subunits and GF14-6 affects grain filling, knockout validation of RPN6, PBD2 (PRC2) and GF14-6 will be performed. In addition, since GF14-6 interacts with the phosphorylated proteins, we will determine the phosphorylation site of HSP90.6. Due to the important role of HSP90 family proteins in plant development, there are other regulatory pathways that need to be explored.

plant biology↗

bioRxiv2022

A Deep SE(3)-Equivariant Model for Learning Inverse Protein Folding

In this work, we establish a framework to tackle the inverse protein design problem; the task of predicting a proteins primary sequence given its backbone conformation. To this end, we develop a generative SE(3)-equivariant model which significantly improves upon existing autoregressive methods. Conditioned on backbone structure, and trained with our novel partial masking scheme and side-chain conformation loss, we achieve state-of-the-art native sequence recovery on structurally independent CASP13, CASP14, CATH4.2, and TS50 test sets. On top of accurately recovering native sequences, we demonstrate that our model captures functional aspects of the underlying protein by accurately predicting the effects of point mutations through testing on Deep Mutational Scanning datasets. We further verify the efficacy of our approach by comparing with recently proposed inverse protein folding methods and by rigorous ablation studies.

bioinformatics↗

bioRxiv2022

Scalable production of recombinant three-finger proteins: from inclusion bodies to high quality molecular probes

We introduce a working pipeline for expression, purification and validation of disulfide-bond rich three-finger proteins using E. coli as the expression host. With this pipeline, we have successfully obtained highly purified and bioactive recombinant -Bungarotoxin, k-Bungarotoxin, Hannalgesin, Mambalgin-1, -Cobratoxin, MT, Slurp1, Pate B etc. Milligrams to hundreds of milligrams of recombinant three finger proteins were obtained within weeks in the lab. The recombinant proteins showed specificity in binding assay and six of them were crystallized and structurally validated using X-ray diffraction protein crystallography. As many three finger proteins have attractive therapeutic or research interests and due to the extremely high quality of the recombinant three finger proteins we obtained, our method provides a competitive alternative to either their native counterparts or chemically synthetic ones, and should facilitate related research and applications.

biochemistry↗

bioRxiv2022

Population genomics unravels the Holocene history of Triticum-Aegilops species

Deep knowledge of crop biodiversity is essential to improve global food security. Despite bread wheat serving as a keystone crop worldwide, the population history of bread wheat and its wild relatives (a.k.a. wheats) remains elusive. By analyzing whole-genome sequences of 795 wheats, we found that bread wheat originated southwest of the Caspian Sea [~]11,700 years ago and underwent a slow speciation process, lasting [~]3,300 years due to persistent gene flow from wild relatives. Soon after, bread wheat spread across Eurasia and reached Europe, South Asia, and East Asia [~]7,000 to [~]5,000 years ago, shaping a diversified but occasionally convergent adaptive landscape of bread wheat in novel environments. Opposite to cultivated wheat, wild wheat populations have declined by [~]82% in the past [~]2,000 years due to the food choice shift of humans, and likely continue to drop because of the changing climate. These findings will guide future efforts in protecting and utilizing wheat biodiversity to improve global food security.

genetics↗

bioRxiv2022

Near-neutral pH increased n-caprylate production in a microbiome with product inhibition of methanogenesis

The pH is a critical parameter in chain-elongating bioreactors, affecting: (1) the concentration of inhibitory undissociated carboxylic acids, which in turn affects the efficiency of product extraction; (2) the thermodynamics; and (3) the kinetics. Here, we examined the effect of five different pH levels (5.5 to 7.0) on n-caprylate (C8) production using an anaerobic sequencing batch reactor (ASBR) with continuous membrane-based liquid-liquid extraction (pertraction). We found that the product spectrum was directed by pH: mildly acidic pH (5-6) led to n-caproate (C6) production, while near-neutral and neutral pH (6.75-7) favored n-caprylate production. In particular, the pH of 6.75 led to the maximum values of volumetric n-caprylate production rate (75.6 {+/-} 0.6 mmol C L-1 d-1; 0.06 g L-1 d-1) and n-caprylate concentration in the fermentation broth (420 mM C; 7.57 g L-1). Given that methane production remained low at near-neutral and neutral pH, we theorized that the high concentration of undissociated n-caprylic acid (5.71 mM C) inhibited methanogenesis. We then demonstrated such an inhibitory effect at neutral pH in: (1) microcosm experiments; and (2) the continuous bioreactor by adding methanogenic sludge. Furthermore, 16S rRNA gene sequencing analysis revealed that near-neutral and neutral pH led to more diverse microbial communities than at mildly-acidic pH. For the first time, we report predominant n-caprylate production in a microbiome at near-neutral and neutral pH conditions where methanogenesis was controlled by the inhibitory effects of undissociated n-caprylic acid. At the same time, extraction of this species occurred even at near-neutral and neutral pH.

bioengineering↗

bioRxiv2022

Medial prefrontal-hippocampal concordance in child-parent dyads underlies children's psychological wellbeing

Family emotional climate is fundamental to childs emotional wellbeing and mental health. Negative family emotional climate may lead to heightened psychopathological symptoms via dysfunctional child-parent interactions. Single-brain paradigms have uncovered changes in brain systems and networks related to negative family environments, but how neurobiological reciprocity between child and parent brains is associated with childrens psychopathological symptoms remains unknown. In study1, we investigated the relationship between family emotional climate and childrens psychopathological symptoms in 395 child-parent dyads. In study2, using a naturalistic movie-watching functional magnetic imaging technique in a subsample of 100 children and parents, we investigate the neurobiological underpinnings of how family emotional climate is associated with childrens psychopathological symptoms through child-parent neural synchrony. Children from negative family emotional climate experienced more severe psychopathological symptoms. We revealed significantly higher inter-subject correlations in the dorsal and ventral portions of the medial prefrontal cortex (mPFC), and greater concordance of activity with widespread brain regions critical for socioemotional skills in child-parent than child-stranger dyads. Critically, negative family emotional climate was associated with decreased inter-subject functional correlation between the ventral mPFC and the hippocampus in child-parent dyads, which further accounted for higher childrens internalizing symptoms especially for anxious and depressed aspects. Family emotional climate might transmit into the brain of parent-child dyads, which may associate with child development outcomes. The present study identified that child-parent vmPFC-hippocampal circuitry is linked to childrens psychopathological symptoms. Our findings suggest a neurobiological mechanism of how negative family emotional climate affects childrens psychopathological symptoms through altered child-parent neural synchrony.

neuroscience↗

bioRxiv2022

LTD-inducing low frequency stimulation enhances p-Tau181 and p-Tau217 in an age-dependent manner in live rats

The progressive cognitive decline in Alzheimers disease (AD) patients correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age-associated. Although elevation of phosphorylated tau (p-Tau) on residues Thr181 (p-Tau181), Thr217 (p-Tau217), and Thr231 (p-Tau231) in cerebrospinal fluid or blood are recently proposed to be particularly sensitive markers of early AD, the generation of p-Tau during brain activity is poorly understood. A major form of synaptic plasticity, long-term depression (LTD), has recently been linked to the enhancement of tau phosphorylation. Here we show that low frequency stimulation (LFS), used to induce LTD, enhances p-Tau181 and p-Tau217 in an age-dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 is less sensitive to LFS. Pharmacological antagonism of either NMDA or metabotropic glutamate 5 (mGluR5) receptors inhibits the elevation of both p-Tau181 and p-Tau217. Targeting ageing with a small molecule cognitive enhancer ISRIB (trans-isomer) prevents the enhancement of p-Tau by LFS in aged rats. Together, our data provide an in vivo means to uncover brain plasticity-related cellular and molecular processes of tau phosphorylation in health and ageing conditions.

neuroscience↗