Biology subjects

Zhang, J.

Publications and source records attributed to Zhang, J..

At least 361 records · Page 20Linked to original sources

bioRxiv2025

Multimodal Data Fusion Reveals Morpho-Genetic Variations in Human Cortical Neurons Associated with Tumor Infiltration

We introduce LetsACT (Light-Electron-Transcriptome synergistic ACTomography), a multimodal integration platform that overcomes the limitations of single-modality data acquisition and analysis of human brain cells while synergistically leveraging the strengths of each modality. Our approach enables the rapid sample preparation, cell injection, imaging, and multimodal integration of large-scale human neuronal datasets at single-cell resolution. By generating initial laser-scanning-microscopy based optical reconstruction of neuron morphologies followed by refining them using electron-microscopy derived morphological priors, we have assembled one of the largest human cortical morphology datasets to date: 8,398 neurons from 58 donors, with high cortical coverage. This platform is then applied to studying morphological impact of tumor infiltration. Pyramidal neurons in glioma-infiltrated tissues display clear volume shrinkage in somas and branches, tapering from the soma to nearby dendritic compartments. By integrating these morphological variations with spatial and bulk transcriptomic profiles, we find that glioblastoma tissues exhibit dysregulation of 15.29% of genes, including overexpression of TERT, whereas infiltrated tissues show 7.74% gene dysregulation, characterized by overexpression of tumor suppressors such as CDKN2A and TP53. Our analysis implies that pyramidal neurons observed in these infiltrated tissues may involve an active defense instead of undergoing passive apoptosis. Our finding also indicates that LetsACT establishes a valuable resource for the large-scale, comprehensive morpho-genetic analysis of human tissues.

neuroscience↗

bioRxiv2025

SF3A2 deacetylation at lysin 10 mitigates myocardial pathological remodeling by reprogramming cardiomyocyte metabolism

BackgroundDysregulation of splicing factor-mediated pre-mRNA alternative splicing (AS) underlies the progression of complex diseases, but the specific involvement of AS in myocardial pathological remodeling remains unclear. This study aimed to elucidate the role of splicing factor 3A, subunit 2 (SF3A2) in the development of myocardial pathological remodeling by regulating AS and its effect on metabolic reprogramming. MethodsWe evaluated the function and mechanism of SF3A2 in myocardial pathological remodeling using murine models induced by myocardial infarction (MI) and isoproterenol. The gain- and loss-of-function models (AAV9-cTNT delivery-mediated knock-in and lentivirus-mediated knockdown) combined with acetylomics, metabolomics, lipidomics, 13C-glucose tracing and immunoprecipitation coupled with liquid chromatography-tandem mass spectrometry (IP-MS) analyses were used to demonstrate the mechanism of SIRT7-mediated SF3A2 deacetylation at lysin 10 (K10). Unbiased RNA sequencing and AS analysis were conducted to identify the downstream effector of SF3A2. ResultsSF3A2 acetylation at lysine 10 was upregulated in cardiomyocytes in response to myocardial pathological remodeling. Functionally, the knock-in of a deacetylation-mimetic SF3A2 (K10R) mutant attenuated myocardial hypertrophy, fibrosis, and improved heart function. These phenotypes were accompanied by a redirection of glucose flux from anaerobic glycolysis to the TCA cycle, along with a promotion of fatty acid {beta}-oxidation by inhibiting CD36 translocation and decreasing ACLY activity. Mechanistically, SF3A2 mitigated metabolic reprogramming and mitochondrial dysfunction by regulating Nnt AS, a process involving the SF3A2-interacting protein Ddx1. IP-MS further identified SIRT7 as the deacetylase for SF3A2, which was found to be activated by ginsenoside Rg1 in a high-throughput screen, leading to improved heart function. ConclusionsOverall, our findings establish the SIRT7-SF3A2-Nnt axis as a critical regulator in metabolic reprogramming to delay pathological myocardial remodeling. Promoting SF3A2 deacetylation, mediated by AAV9 delivery or pharmacological activation of SIRT7, improved heart function, suggesting its potential as a therapeutic target for pathological myocardial remodeling.

molecular biology↗

bioRxiv2025

Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation

Nuclear Factor I (NFI) misexpressions in humans are associated with severe brain malformations, yet the underlying mechanisms remain poorly understood. Here we show that NFIs regulate the broad lineage progression and lifespan of radial glial progenitors (RGPs), and consequently neocortical development in a dose-dependent manner. Human cerebral organoids carrying patient-mimicking NFI mutations exhibit expression level-dependent bidirectional impairments in RGP temporal development, coinciding with patient phenotypes. In mouse models, selective removal of NFIs leads to a dramatic protraction of RGP lineage progression and lifespan, excessive progeny output, and neocortical overgrowth and abnormal folding, whereas overexpression of NFIs accelerates RGP lineage progression, resulting in developmental stage-dependent precocious productions of diverse neural progenies. Moreover, NFIs exhibit a positive auto-regulation and progressive increase in expression, and regulate distinct temporal-specific targets underlying RGP lineage progression. These results suggest that NFIs act as evolutionarily conserved key global temporal regulators of RGP lineage progression and neocortical development. HIGHLIGHTSO_LINFIs affect human RGP temporal development coinciding with patient phenotypes. C_LIO_LINFI removal protracts RGP lineage progression and lifespan with excessive progeny output. C_LIO_LINFI overexpression accelerates RGP lineage progression with precocious progeny output. C_LIO_LINFIs regulate distinct temporal-specific targets underlying RGP lineage progression. C_LI

neuroscience↗

bioRxiv2025

Fully computational design of PAM-relaxed Staphylococcus aureus Cas9 with expanded targeting capability

CRISPR-Cas9 nucleases have transformed genome engineering, yet their application is often constrained by protospacer-adjacent motif (PAM) requirements. Staphylococcus aureus Cas9 (SaCas9) is particularly attractive for in vivo applications due to its compact size; however, its NNGRRT PAM limits targetable genomic sites. Here, we report KRH, a SaCas9 variant designed entirely from the wild-type enzyme through a fully computational point-mutation design workflow, UniDesign, without additional experimental optimization. As expected, KRH efficiently recognizes an expanded NNNRRT PAM and exhibits substantially enhanced editing efficiency at non-canonical PAM sites, with improvements of up to 116-fold over the wild type. KRH achieves genome- and base-editing efficiencies comparable to, or exceeding, those of the well-known evolution-derived KKH variant. Computational modeling by UniDesign provides a mechanistic explanation for the PAM relaxation observed in both KRH and KKH, with structural and energetic analyses revealing that KRH relaxes PAM specificity by fine-tuning the balance between sequence-specific interactions with PAM bases and nonspecific contacts with the DNA backbone. Beyond its practical utility, KRH demonstrates that computational design can identify a minimal set of mutations sufficient to remodel the PAM interface while preserving high nuclease activity. This approach recapitulates--and in some cases surpasses--the performance of evolution-derived variants, offering a scalable strategy for high-throughput Cas9 engineering. Overall, these results establish KRH as a blueprint for rationally engineered, PAM-relaxed nucleases and underscores the power of computational design to accelerate next-generation genome editing.

bioengineering↗

bioRxiv2025

Mouse Cardiac Regeneration Database (MCAREDB): a single-cell atlas of neonatal cardiac regeneration in mice

BackgroundThe adult mammalian heart exhibits minimal regenerative capacity, rendering most major cardiac injuries irreversible. In contrast, neonatal mice retain the ability to regenerate cardiac tissue for a brief period after birth. Although single-cell RNA sequencing (scRNA-seq) has deepened our understanding of this regenerative window, existing datasets remain dispersed across studies, hindering integrative and comparative analyses. Methods and ResultsTo address this gap, we developed the Mouse CArdiac REgeneration DataBase (MCAREDB), a freely accessible, web-based resource that consolidates scRNA-seq datasets from multiple mouse cardiac regeneration studies. MCAREDB enables cell type-specific exploration of differential gene expression and pathway enrichment across key biological contexts, including neonatal versus postnatal stages and sham versus myocardial infarction surgeries. Core features include an interactive genome browser with epigenetic tracks, comparative gene expression visualization, pathway enrichment analysis, and bulk data download options. ConclusionBy integrating diverse datasets into a unified and interactive framework, MCAREDB lowers technical barriers to data exploration and accelerates hypothesis generation in cardiac regeneration research. The resource is freely available at https://MCAREDB.org:3305.

bioinformatics↗

bioRxiv2025

Influence of phosphate activation chemistry on the selection of the primordial genetic alphabet

RNA copying under mild conditions compatible with protocell integrity requires the input of chemical energy to drive the synthesis of activated nucleotides such as phosphorimidazolides. Recently, two potentially prebiotic classes of phosphate-activating agents have been explored, one based on isonitrile-aldehyde chemistry, the other on imine diimidazole (IDI)-N-cyanoimidazole (NCI) chemistry. Because such highly electrophilic activating agents may lead to undesirable nucleotide modifications, we have examined the reaction of both types of activating agents with the canonical ribonucleotides A, U, C, and G, and the potentially primordial nucleotides 2-thio-C (s2C), 2-thio-U (s2U), and inosine (I). We find that the isonitrile-aldehyde system shows minimal hydroxyl modification but does modify the nucleobases of U, G, s2U, and I. Except for guanosine, these modifications are readily reversible. In contrast, IDI-NCI systems acylate ribonucleotide hydroxyls while modifying nucleobases only transiently; mildly acidic pH suppresses undesired modifications. Both classes of activating agents modify 2-thiopyrimidines on the sulfur, with the isonitrile-aldehyde reaction promoting desulfurization and thus conversion to the canonical pyrimidines. To evaluate compatibility with model protocells, we tested the effects of activation chemistry on fatty acid vesicles and found that protocell integrity was preserved at moderate reagent concentrations. Our findings show that the potentially primordial s2U, s2C, and I nucleotides are more sensitive to modification than the canonical U, C, and G nucleotides, potentially contributing to the chemical selection of the early genetic alphabet.

biochemistry↗

bioRxiv2025

Sampling Function-Related Metastable States of Proteins With DASH

Rational discovery of function-specific protein modulators as well as activity-enhanced engineering proteins underscore the need to identify function-related metastable states (FMSs) of proteins. However, current experimental and computational methods struggle to generate these states directly from their native state (NS), likely because the NS [->] FMS transition is non-spontaneous. To address this challenge, we introduce Deep learning guided Adaptive sampling with seed Selection and Hopping (DASH), integrating both deep learning and physical functions to guide molecular dynamics (MD) simulation towards FMS. DASH successfully sampled NS [->] FMS transitions in 18 cases across two tasks: protein activation and cryptic allosteric site opening. DASH combined with secondary-structure collective variables is further able to sample folding of disordered regions. Compared to existing methods, DASH demonstrates superior performance while requiring comparable simulation time. Crucially, we applied DASH to sample new conformations of proteins, by which revealing new folding states, previously unknown allosteric sites, and potential activators. These predictions have been further verified in wet-lab experiments and crystal structures determinations. Collectively, our framework provides a robust strategy for function-specific pharmacy research and could accelerate future drug discovery efforts.

bioinformatics↗

bioRxiv2025

Efficient Generation of Humanized Cloned Cattle via Embryonic Stem Cell-Mediated Dual-Round Site-Specific Editing

Transgenic cloning allows genetic modification in cattle, yet its translational potential is constrained by low cloning efficiency and limited gene-editing capacity, due largely to the restricted proliferative ability of somatic donor cells. Pluripotent stem cells (PSCs), with their unlimited self-renewal ability, represent a promising alternative to overcome these bottlenecks. Here, we first established stable bovine epiblast stem cell lines (bEpiSCs) and achieved site-specific integration of the HCSN2-HLF-GFP cassette into the {beta}-casein locus, with high transfection (72.07%) and correct integration efficiency (80.48%). Following Cre LoxP mediated excision of the selectable marker, we obtained marker free HCSN2-HLF bEpiSCs that retained pluripotency markers, tri lineage differentiation potential, and supported target protein expression in immortalized bovine mammary epithelial cells. When used as nuclear donors, these cells produced blastocysts with quality comparable to in vitro fertilization (IVF) embryos. Notably, cloning with HCSN2-HLF bEpiSCs resulted in the birth of twelve calves, with significantly higher birth and survival rates (30.71% and 16.74%, respectively) than those obtained using fibroblasts. Both PCR-based genotyping of the edited loci and microsatellite kinship analysis confirmed that all cloned calves were genetically derived from the HCSN2-HLF bEpiSCs. Collectively, this study establishes an efficient embryonic stem cell based platform for targeted gene editing and rapid production of multigene edited cloned cattle, offering a scalable strategy with strong potential for industrial translation.

bioengineering↗

bioRxiv2025

Plasma Induced Afterglow Luminescence

Afterglow imaging, is an emerging optical modality using agents that emit persistent luminescence after excitation ceases to eliminate tissue auto fluorescence and improve signal-to-background ratios. However, there was limited number of organic matters could produce persistent luminescence when using light, ultrasound or ionizing radiation as the excitation source. Herein, we explored cold atmospheric plasma (CAP) as a universal and exclusive stimulus for activating intense and long-lasting afterglow from widely-exist organic matters, which could not easily excited by light, ultrasound or X-ray radiation. Furthermore, we demonstrated the biomedical applications of the CAP-induced long-lasting afterglow for photodynamic residual removal after surgical resection of tumor. It should be point out that using CAP as the excitation source might opened new avenue for afterglow imaging clinical translation based on some FDA-approval organic matters learning from the drug repurposing strategy.

biochemistry↗

bioRxiv2025

An accurate phasing tool via high-quality heterozygous variations

Long-read phasing has become a widely adopted approach for reconstructing paternal and maternal haplotypes in diploid genomes. However, most existing phasing methods treat all variants equally, even though low-quality variants frequently introduce switch errors. We present a new phasing method, snpphaser, which first phases high-quality variants and then leverages them to filter out low-quality variants that are inconsistent with the high-confidence haplotypes. We benchmarked snpphaser against state-of-the-art phasing methods across nine diverse datasets. The results demonstrate that snpphaser achieves superior contiguity and accuracy compared to existing approaches.

bioinformatics↗

bioRxiv2025

MultiGAI: Global Attention-Based Integration of Single-Cell Multi-Omics with Batch Effects Correction

Single-cell multi-omics technologies allow the simultaneous measurement of multiple molecular modalities within the same cell, such as gene expression and chromatin accessibility (scRNA-seq + scATAC-seq) or gene expression and cell surface protein abundance (scRNA-seq + ADT), providing a multidimensional perspective on cellular states and regulatory mechanisms. However, these modalities often differ substantially in their distributions and noise levels and are affected by technical biases during experimental batches and sample processing, which can obscure true biological signals. To address these challenges, we present Multi-GAI, a variational autoencoder (VAE) framework with a global attention mechanism. MultiGAI integrates global information from the dataset during encoding and employs specially designed components to limit the propagation of batch information. This design allows effective batch effects correction while preserving key biological signals, generating high-quality latent representations of cells. Notably, in addition to performing well on single-cell multi-omics data, MultiGAI also demonstrates good performance in batch effects correction for single-cell transcriptomic data and in the integration of spatial transcriptomic data. Overall, MultiGAI provides a novel strategy for batch effects correction while retaining biological information, offering new insights for future single-cell multi-omics data integration.

bioinformatics↗

bioRxiv2025

Human trunk embryoids with patterned anterior-posterior and dorsal-ventral body axes: utility for understanding human development and disease

Human embryoid models enable mechanistic studies of development and disease. We generated trunk embryoids from human pluripotent stem cells that recapitulate posterior trunk formation at Carnegie stage (CS) 8-10, with patterned anterior-posterior (A-P) and dorsal-ventral (D-V) axes. These self-organizing structures comprise a ventral notochord, dorsal neural tube, floor plate and bilateral somites. Genetic and chemical perturbations of SHH signaling confirmed the notochords central role in D-V patterning. Moreover, VANGL1/2 loss-of-function mutations recapitulated mouse phenotypes, including axial truncation and somite segmentation failure. This model enables detailed study of key developmental events that underlie posterior trunk formation and provides a promising platform for human disease modeling.

developmental biology↗

bioRxiv2025

A division-associated envelope protein, MAB_2363, drives intrinsic resistance and virulence in Mycobacterium abscessus

Mycobacterium abscessus exhibits intrinsic resistance to conventional antibiotics, significantly limiting treatment options. Our previous studies established that MAB_2362 (SteA) is a key regulator of cell division that contributes to intrinsic resistance and virulence. Considering that SteA-like proteins often act alongside SteB counterparts, we hypothesized that the adjacent gene MAB_2363 encodes the corresponding SteB-like division regulator. In this study, we found that deletion of MAB_2363 significantly increased susceptibility to multiple antibiotics and disrupted cell wall permeability. Microscopy revealed striking cell division defects in the mutant, including elongated cell morphology and multiple septa. Subcellular localization of a GFP-MAB_2363 fusion protein demonstrated its enrichment at division septa, confirming its direct involvement in cell division. Deletion of MAB_2363 resulted in attenuated virulence, as evidenced by reduced bacterial survival in macrophages and murine infection models. To assess its functional relation with MAB_2362, we compared the single-deletion mutant of MAB_2363 with the single-deletion mutant of MAB_2362 and the double-deletion mutant of MAB_2362-MAB_2363. Notably, the phenotypes of the MAB_2363 mutant, including cell division defects, antibiotic susceptibility, and virulence, were markedly milder than those of the other two mutants. Collectively, these findings indicate that MAB_2363 functions as a secondary but essential division-associated factor that operates during cell division, thereby influencing intrinsic resistance and virulence in M. abscessus.

microbiology↗

bioRxiv2025

Functional Characterization of 123 Genes from Mycobacteriophage LeBron Uncovers Cytotoxic Gene Families in Cluster L1

Bacteriophages represent a vast reservoir of genetic diversity however, functional annotation remains a major challenge, as most predicted gene products lack detectable similarity to characterized gene families. Experimental approaches such as systematic overexpression screens provide an avenue for identifying phage genes that influence bacterial physiology. Here, we report an overexpression screen of all 123 predicted protein-coding genes from Cluster L1 mycobacteriophage LeBron, the first representative of this cluster to undergo genome-wide functional analysis. Expression assays in Mycobacterium smegmatis revealed that 39 genes (32%) impaired host growth, with nineteen of these toxic genes (49%) assigned no known function. The proportion of cytotoxic genes observed in LeBron is comparable to findings from Clusters K and F, despite minimal sequence conservation across clusters. Interestingly, a subset of LeBrons toxic genes appear to be functionally analogous to previously identified toxic genes in other clusters, suggesting conserved biological activities carried out by non-homologous proteins. Additionally, this analysis uncovered several novel gene families that elicit strong cytotoxic effects, expanding the known catalog of phage-derived bacterial growth inhibitors. These results provide new insights into phage gene functions and demonstrate the value of genome-wide expression screening for uncovering conserved and cluster-specific interactions between bacteriophages and their hosts.

microbiology↗

bioRxiv2025

Genomic Structural Variation Underlies Cell-Type-Specific Betacyanin Variegation in Chenopodium quinoa

The allotetraploid crop quinoa (Chenopodium quinoa) accumulates red/violet betacyanins, which function as vital stress-mitigating antioxidants. We investigated the genetic basis of red/green variegation observed in the aerial organs of the P0429 accession. We demonstrated that this color mosaic is primarily localized to the epidermal bladder cells (EBCs), with red EBCs accumulating [~]50-fold higher betacyanin levels than colorless EBCs. Cell-type-specific RNA-sequencing of EBCs identified the cytochrome P450 gene Cqu0091301 (CYP76AD) as the dominant and rate-limiting factor, exhibiting strong upregulation in red EBCs. This high pigmentation requires a specific structural variation in the P0429 accession: a [~]4-kb genomic insertion that restores the full functionality of Cqu0091301, which is otherwise truncated and non-functional in common reference genomes. Genomic analysis reveals that Cqu0091301 is part of a CYP76AD-DODA gene cluster. Notably, expression analysis revealed functional divergence between the quinoa subgenomes, with B-subgenome CYP76AD genes highly dominant in EBCs, while A-subgenome homologs were preferentially expressed in other tissues. Our results establish a clear link between structural genomic variation and cell-type-specific betalain biosynthesis, providing molecular insight into pigment regulation and subgenome specialization in allotetraploid quinoa.

plant biology↗

bioRxiv2025

MFAP5 Drives Elastic Fiber Disorganization to Promote Pulmonary Fibrosis

BACKGROUNDElastic fibers (EF) disorganization contributes to increased tissue stiffness and impaired lung function in pulmonary fibrosis (PF). However, the complex structural features of EF are difficult to capture using conventional histology. Moreover, the molecular mechanisms governing EF homeostasis during fibrosis remain poorly understood. METHODSA high-dimensional Elastic Fiber Algorithm (EFA) was developed to digitally quantify EF structural features in PF. Gene variation-rate analysis was performed to identify candidate regulators of EF homeostasis. Fibroblast-specific and pathological fibroblast-specific MFAP5 knockout mice were generated to assess the role of MFAP5 in PF rodent models. Bulk RNA sequencing was employed to investigate MFAP5-mediated fibroblast activation and signaling pathways. RESULTSEFA revealed profound EF disorganization in fibrotic lungs, capturing various architectural alterations. Gene variation-rate analysis identified MFAP5 as a candidate regulator of EF homeostasis, with upregulated expression in PF patients and mouse models. Fibroblast-specific deletion of MFAP5 significantly attenuated fibrosis, restored EF architecture, reduced collagen deposition, and improved pulmonary function in PF mouse models. MFAP5-positive fibroblasts displayed a dynamic shift toward pathological states during PF progression. Mechanistically, MFAP5 promoted fibroblast activation and ECM production via v{beta}3 integrin-mediated TGF{beta} signaling. CONCLUSIONSMFAP5 is a key orchestrator of EF remodeling and fibroblast activation in PF. Targeting MFAP5 restores EF homeostasis, reduces fibrotic severity, and represents a potential therapeutic strategy for PF.

molecular biology↗

bioRxiv2025

Identification of the protein precursor for thyroid hormone synthesis in the basal chordate ascidian Styela clava

Thyroid hormones (THs) play crucial roles in development, growth, and metabolism across the animal kingdom1,2. Although the mechanism of TH synthesis in vertebrates has been well described, it remains elusive in invertebrates due to the lack of identified orthologs of the thyroglobulin (TG), the protein precursor for TH synthesis3,4. Here, we identified a functional TG protein encompassing multiple TG type 1 (Tg1)-domains, encoded by the ScTg-like gene in proto-vertebrate ascidian Styela clava based on the immunoprecipitation-mass spectrometry combined with phylogenetic and expression pattern analyses. In vitro iodination experiments demonstrated that ScTG-like has the capacity to provide hormonogenic sites for TH synthesis. Furthermore, in vivo gene knockdown of ScTg-like revealed that the larval metamorphosis was significantly inhibited as a consequence of diminished TH levels, indicating that ScTg-like is responsible for the production of endogenous TH. Additionally, an invaginated follicle-like structure was first discovered at the central anterior of the larval trunk where both ScTG-like protein and THs were deposited, suggesting that this structure serves as the location for THs synthesis and storage, functionally similar to vertebrate thyroid follicles. Moreover, we analyzed the structural features of ScTG-like protein and detected the similarly organized Tg1-containing proteins in multiple bilaterian phyla, suggesting that endogenous TH synthesis may be an ancestral, possibly synapomorphic, trait of bilaterians. Our study is the first to identify the TH protein precursor outside vertebrates by providing the direct evidence of endogenous de novo TH synthesis, which offers insights into the evolution of TG protein and the emergence of a major vertebrate endocrine system.

evolutionary biology↗

bioRxiv2025

Selective Inactivation of Astrocytic Monoacylglycerol Lipase for Alzheimer Disease Therapy

Alzheimers disease (AD) is the leading cause of dementia in the elderly, yet effective therapies remain lacking. Here, we identify monoacylglycerol lipase (MAGL), the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, specifically in astrocytes as a promising therapeutic target for AD. APP transgenic (TG) mice with astrocyte-specific MAGL deletion (TG-aKO), but not neuron-specific deletion (TG-nKO), exhibit markedly reduced A{beta} pathology, neurodegeneration, and neuroinflammation, along with preserved synaptic structure and function and improved cognition. These benefits are recapitulated in TG mice by AAV-mediated silencing of astrocytic MAGL, whereas MAGL overexpression exacerbates neuropathology and accelerates synaptic and cognitive decline. Transcriptomic analyses reveal that dysregulated synapse-, inflammation-, and AD-related gene expression profiles are reversed in TG-aKO mice. MAGL expression is elevated in astrocytes from both AD patients and TG mice. Remarkably, a single intracerebroventricular (ICV) injection of AAV-MAGL-shRNA administered at either presymptomatic or postsymptomatic stages prevents or reverses neuropathology and synaptic and cognitive impairments in TG mice, providing preclinical evidence that astrocytic MAGL silencing represents an effective therapeutic strategy for AD.

neuroscience↗