Biology subjects

Gan, L.

Publications and source records attributed to Gan, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC lines to express 4R-tau and 4R-tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes, including shared transcriptomic signatures, autophagic body accumulation, and impaired neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of Tau-seeding-induced Tau propagation, including retromer VPS29 and the UFMylation cascade as top modifiers. In AD brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade suppressed seeding-induced Tau propagation. This model provides a powerful platform to identify novel therapeutic strategies for 4R tauopathy.

neuroscience↗

bioRxiv2023

CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis

Aggregation of the protein tau is a hallmark of Alzheimers disease and other tauopathies. Specific neuronal subtypes are selectively vulnerable to tau aggregation, but the underlying mechanisms are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen in iPSC-derived neurons. The screen uncovered expected pathways, including autophagy, but also unexpected pathways, including UFMylation and GPI anchor synthesis, that control tau oligomer levels. We discover that the E3 ubiquitin ligase CUL5SOCS4 is a potent modifier of tau levels in human neurons, ubiquitinates tau, and is correlated with resilience to tauopathies in human disease. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, which generates tau proteolytic fragments like those in disease and changes tau aggregation in vitro. These results reveal new principles of tau proteostasis in human neurons and pinpoint potential therapeutic targets for tauopathies.

cell biology↗

bioRxiv2023

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimers disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase M{zeta} (PKM{zeta}) to maintain synaptic plasticity and memory despite tau mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

neuroscience↗

bioRxiv2023

Neural extracellular matrix regulates visual sensory motor integration

Visual processing depends on sensitive and balanced synaptic neurotransmission. Extracellular matrix proteins in the environment of cells are key modulators in synaptogenesis and synaptic plasticity. In the present study, we provide evidence that the combined loss of the four extracellular matrix components brevican, neurocan, tenascin-C and tenascin-R in quadruple knockout mice leads to severe retinal dysfunction and diminished visual motion processing in vivo. Remarkably, impaired visual motion processing was accompanied by a developmental loss of cholinergic direction-selective starburst amacrine cells. Additionally, we noted imbalance of inhibitory and excitatory synaptic signaling in the quadruple knockout retina. Collectively, the study offers novel insights into the functional importance of four key extracellular matrix proteins for retinal function, visual motion processing and synaptic integrity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/537074v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@eec571org.highwire.dtl.DTLVardef@1e4b282org.highwire.dtl.DTLVardef@18398a7org.highwire.dtl.DTLVardef@9b113b_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefIn their study, Reinhard et al. show that the combined loss of the extracellular matrix components brevican, neurocan, tenascin-C and tenascin-R in quadruple knockout mice leads to retinal dysfunction, diminished visual motion processing, developmental loss of cholinergic direction-selective starburst amacrine cells and imbalance of inhibitory and excitatory synaptic integrity. HighlightsO_LICombined loss of the four extracellular matrix molecules brevican, neurocan, tenascin-C and tenascin-R causes retinal dysfunction C_LIO_LIImpaired visual motion processing in quadruple, tenascin-C and tenascin-R knockout mice C_LIO_LILoss of cholinergic direction-selective starburst amacrine cells in the quadruple knockout retina C_LIO_LIThe matrisome influences inhibitory and excitatory synaptic balance C_LI

neuroscience↗

bioRxiv2023

Transformation of primary murine peritoneal mast cells by constitutive KIT activation as a result of lost Cdkn2a/Arf expression

Mast cells (MCs) are immune cells of the myeloid lineage distributed in tissues throughout the body. Phenotypically, they are a heterogeneous group characterized by different protease repertoires stored in secretory granules and differential presence of receptors. To adequately address aspects of MC biology either primary MCs isolated from human or mouse tissue or different human MC lines, like HMC-1.1 and -1.2, or rodent MC lines like L138.8A or RBL-2H3 are frequently used. Nevertheless, cellular systems to study MC functions are very limited. We have generated a murine connective tissue-like MC line, termed PMC-306, derived from primary peritoneal MCs (PMCs), which spontaneously transformed. We analyzed PMC-306 cells regarding MC surface receptor expression, effector functions and respective signaling pathways, and found that the cells reacted very similar to primary wildtype (WT) PMCs. In this regard, stimulation with MAS-related G-protein-coupled receptor member B2 (MRGPRB2) ligands induced respective signaling and effector functions. Furthermore, PMC-306 cells revealed significantly accelerated cell cycle progression, which however was still dependent on IL-3 and stem cell factor (SCF). Phenotypically, PMC-306 cells adopted an immature connective tissue-like MCs appearance. The reason for immortalization most likely is the loss of the two critical cell cycle regulators Cdkn2a/INK4A and Arf/p19, respectively. The loss of Cdkn2a and Arf expression could be mimicked in primary bone marrow-derived mast cells (BMMCs) by SCF supplementation strongly arguing for an involvement of KIT activation in the transformation process. Hence, this new cell line might be a useful tool to study further aspects of PMC function and to address tumorigenic processes associated with MC leukemia.

immunology↗

bioRxiv2022

CTCF mediates the Activity-by-contact derived cis-regulatory hubs

The 3D chromatin architecture establishes a complex network of genes and regulatory elements necessary for transcriptomic regulation in development and disease. This network can be modelled by cis-regulatory hubs (CRH), which underscore the local functional interactions between enhancers and promoter regions and differ from other higher-order chromatin structures such as topologically associated domains (TAD). The Activity-by-contact (ABC) model of enhancer-promoter regulation has been recently used in the identification of these CRHs, but little is known about the role of CTCF on the ABC scores and the consequent impact on CRHs. Here we show that the loss of CTCF leads to a reorganization of the ABC-derived rankings of the putative enhancers in the mouse heart, a global reduction of the total number of CRHs and an increase in the size of the CRHs. Furthermore, CTCF loss leads to a higher percentage of CRHs that cross TAD boundaries. These results provide another layer of evidence to support the importance of CTCF in the formation of regulatory networks necessary for gene regulation. SummaryDeletion of CTCF in mouse cardiomyocytes led to reorganization of the activity-by-contact scores of the heart enhancers and changes in the cis-regulatory hubs

molecular biology↗

bioRxiv2022

GESIAP: A Versatile Genetically Encoded Sensor-based Image Analysis Program

Intercellular communication mediated by a large number of neuromodulators diversifies physiological actions, yet neuromodulation remains poorly understood despite the recent upsurge of genetically encoded transmitter sensors. Here, we report the development of a versatile genetically encoded sensor-based image analysis program (GESIAP) that utilizes MATLAB-based algorithms to achieve high-throughput, high-resolution processing of sensor-based functional imaging data. GESIAP enables delineation of fundamental properties (e.g., transmitter spatial diffusion extent, quantal size, quantal content, release probability, pool size, and refilling rate at single release sites) of transmission mediated by various transmitters (i.e., monoamines, acetylcholine, neuropeptides, and glutamate) at various cell types (i.e., neurons, astrocytes, and other non-neuronal cells) of various animal species (i.e., mouse, rat, and human). Our analysis appraises a dozen of newly developed transmitter sensors, validates a conserved model of restricted non-volume neuromodulatory synaptic transmission, and accentuates a broad spectrum of presynaptic release properties that variegate neuromodulation.

neuroscience↗

bioRxiv2022

A global view of aging and Alzheimer's pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

Conventional single-cell genomics approaches are limited by throughput and thus may have failed to capture aspects of the molecular signatures and dynamics of rare cell types associated with aging and diseases. Here, we developed EasySci, an extensively improved single-cell combinatorial indexing strategy, for investigating the age-dependent dynamics of transcription and chromatin accessibility across diverse brain cell types. We profiled [~]1.5 million single-cell transcriptomes and [~]400,000 single-cell chromatin accessibility profiles across mouse brains spanning different ages, genotypes, and both sexes. With a novel computational framework designed for characterizing cellular subtypes based on the expression of both genes and exons, we identified > 300 cell subtypes and deciphered their underlying molecular programs and spatial locations especially for rare cell types (e.g., pinealocytes, tanycytes). Leveraging these data, we generated a global readout of age-dependent changes at cell subtype resolution, providing insights into cell types that expand (e.g., rare astrocytes and vascular leptomeningeal cells in the olfactory bulb, reactive microglia, and oligodendrocytes) or are depleted (e.g., neuronal progenitors, neuroblasts, committed oligodendrocyte precursors) as age progresses. Furthermore, we explored cell-type-specific responses to genetic perturbations associated with Alzheimers disease (AD) and identified rare cell types depleted (e.g., mt-Cytb+, mt-Rnr2+ choroid plexus epithelial cells) or enriched (e.g., Col25a1+, Ndrg1+ interbrain and midbrain neurons) in both AD models. Key findings are consistent between males and females, validated across the transcriptome, chromatin accessibility, and spatial analyses. Finally, we profiled a total of 118,240 single-nuclei transcriptomes from twenty-four post-mortem human brain samples derived from control and AD patients, revealing highly cell-type-specific and region-specific gene expression changes associated with AD pathogenesis. Critical AD-associated gene signatures were validated in both human and mice. In summary, these data comprise a rich resource for exploring cell-type-specific dynamics and the underlying molecular mechanisms in normal and pathological mammalian aging.

genomics↗

bioRxiv2022

From multi-omics data to the cancer druggable genediscovery: a novel machine learning-based approach

The development of targeted drugs allows precision medicine in cancer treatment and achieving optimal targeted therapies. Accurate identification of cancer drug genes is helpful to strengthen the understanding of targeted cancer therapy and promote precise cancer treatment. However, rare cancer-druggable genes have been found due to the multi-omics datas diversity and complexity. This study proposes DF-CAGE, a novel machine learning-based method for cancer-druggable gene discovery. DF-CAGE integrated the somatic mutations, copy number variants, DNA methylation, and RNA-Seq data across ~10000 TCGA profiles to identify the landscape of the cancer-druggable genes. We found that DF-CAGE discovers the commonalities of currently known cancer-druggable genes from the perspective of multi-omics data and achieved excellent performance on OncoKB, Target, and Drugbank data sets. Among the ~20,000 protein-coding genes, DF-CAGE pinpointed 465 potential cancer-druggable genes. We found that the candidate cancer druggable genes (CDG-genes) are clinically meaningful and can be divided into highly reliable, reliable, and potential gene sets. Finally, we analyzed the contribution of the omics data to the identification of druggable genes. We found that DF-CAGE reports druggable genes mainly based on the CNAs data, the gene rearrangements, and the mutation rates in the population. These findings may enlighten the study and development of new drugs in the future.

bioinformatics↗

bioRxiv2022

The transcription regulator Lmo3 is required for cell fate specification in the external globus pallidus.

The external globus pallidus (GPe) is an essential component of the basal ganglia, a group of subcortical nuclei that are involved in control of action. Changes in the firing of GPe neurons are associated with both passive and active body movements. Aberrant activity of GPe neurons has been linked to motor symptoms of a variety of movement disorders, such as Parkinsons Disease, Huntingtons disease and dystonia. Recent studies have helped delineate functionally distinct sub types of GABAergic GPe projection neurons. However, little remains known about specific molecular mechanisms underlying the development of GPe neuronal subtypes. We show that the transcriptional regulator Lmo3 is required for the development of medial ganglionic eminence derived Nkx2.1+ and PV+ GPe neurons, but not FoxP2+ neurons or Npas1+ neurons. As a consequence of the reduction in PV+ neurons, Lmo3-null mice have a reduced pallidal input to the subthalamic nucleus. SIGNIFICANCE STATEMENTThe external globus pallidus (GPe) is a critical component of the basal ganglia and can coordinate neuronal activity across the basal ganglia by virtue of its widespread projections to almost all other basal ganglia nuclei. Aberrant activity of GPe neurons has been linked to motor symptoms of a wide variety of movement disorders. Recent advances have delineated functionally distinct sub types of GABAergic GPe projection neurons. However, little remains known about molecular mechanisms underlying their development. Here, we demonstrate that the transcription regulator Lmo3 is required for the development of specific subtypes of GPe neurons, and for their appropriate connectivity with other parts of the basal ganglia.

neuroscience↗

bioRxiv2022

An Inducible Cre Mouse with Preferential Activity in Vascular Smooth Muscle Evades a Previously Lethal Intestinal Phenotype

All smooth muscle cell (SMC) restricted Cre mice recombine floxed alleles in vascular and visceral SMCs. We generated a new tamoxifen-inducible CreERT2 mouse, Itga8-CreERT2, and compared its activity to the widely used Myh11-CreERT2 mouse. Both CreERT2 mice showed similar activity in vascular SMCs; however, Itga8-CreERT2 displayed limited activity in visceral SMC-containing tissues (e.g., intestine). Myh11-CreERT2 (but not Itga8-CreERT2) mice displayed high levels of CreERT2 protein, tamoxifen-independent activity, and an altered transcriptome. Whereas Myh11-CreERT2-mediated knockout of Srf resulted in a lethal intestinal phenotype, loss of Srf with Itga8-CreERT2 (SrfItga8) revealed viable mice with attenuated vascular SMC contractile gene expression, but no evidence of intestinal pathology. Male and female SrfItga8 mice presented with vascular contractile incompetence; however, only male SrfItga8 mice showed systemic changes in blood pressure. These results establish the Itga8-CreERT2 mouse as an alternative to existing SMC Cre strains, including Myh11-CreERT2, where SMC gene loss results in visceral myopathies that obfuscate accurate phenotyping in vascular SMCs.

genetics↗

bioRxiv2021

Single-nuclei isoform RNA sequencing reveals combination patterns of transcript elements across human brain cell types

Single-nuclei RNA-Seq is being widely employed to investigate cell types, especially of human brain and other frozen samples. In contrast to single-cell approaches, however, the majority of single-nuclei RNA counts originate from partially processed RNA leading to intronic cDNAs, thus hindering the investigation of complete isoforms. Here, using microfluidics, PCR-based artifact removal, target enrichment, and long-read sequencing, we developed single-nuclei isoform RNA-sequencing ( SnISOr-Seq), and applied it to the analysis of human adult frontal cortex samples. We found that exons associated with autism exhibit coordinated and more cell-type specific inclusion than exons associated with schizophrenia or ALS. We discovered two distinct modes of combination patterns: first, those distinguishing cell types in the human brain. These are enriched in combinations of TSS-exon, exon-polyA site, and distant (non-adjacent) exon pairs. Second, those with all isoform combinations found within one neural cell type, which are enriched in adjacent exon pairs. Furthermore, adjacent exon pairs are predominantly mutually associated, while distant pairs are frequently mutually exclusive. Finally, we observed that human-specific exons are as tightly coordinated as conserved exons, pointing to an efficient evolutionary mechanism underpinning coordination. SnISOr-Seq opens the door to single-nuclei long-read isoform analysis in the human brain, and in any frozen, archived or hard-to-dissociate sample.

genomics↗

bioRxiv2021

The Isl1/Shh/Wnt5a cascade controls the invasion of myoblasts by tuning the CXCL12/CXCR4 axis during tongue morphogenesis

The migration and invasion of myoblast cells derive from the occipital somites is critical for tongue morphogenesis. However, the molecular mechanisms underlying myoblast migration and invasion remain elusive. In this study, we report that transcription factor Isl1 is required for tongue development. Loss of Isl1 in the distal mandibular epithelium results in aglossia due to the defect of myoblast cells invasion. In the absence of Isl1 expression, myoblast cells in the first branchial arch fail to migrate into the presumptive tongue primordium. Down-regulation of Shh was detected in the distal mandibular epithelium after Isl1 deletion. As a downstream target gene of Shh, Wnt5a attracts the migration of mesenchymal cells expressing chemokine ligand 12 (CXCL12). CXCL12+ mesenchymal cells in the Isl1 mutant embryo fail to migrate to the distal region but accumulate in a relatively small proximal domain of the first branchial arch. CXCL12 serves as a bidirectional cue for myoblasts that express its receptor CXCR4, attracting CXCR4+ myoblasts invasion at low concentration but repelling at high concentration. The defect in the distal migration of CXCL12+ mesenchymal cells leads to a high local concentration of CXCL12, thereby preventing the invasion of CXCR4+ myoblasts. In addition, transgenic activation of Ihh alleviates the defect in tongue development and rescues the invasion of myoblasts, corroborating the functional involvement of Hedgehog signaling in tongue development. In summary, this study provides the first line of genetic evidence for the Isl1/Shh/Wnt5a cascade to regulate myoblasts invasion by tuning the CXCL12/CXCR4 axis.

developmental biology↗

bioRxiv2021

Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease

Tau (MAPT) drives neuronal dysfunction in Alzheimers disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established activity-dependent interactions of Tau with presynaptic vesicle proteins during Tau secretion and mapped the exact APEX-tau-induced biotinylated tyrosines to the cytosolic domains of the interacting vesicular proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Taus interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multi-modal and dynamic Tau interactomes with unprecedented spatiotemporal resolution shed novel insights into Taus role in neuronal function and disease-related processes with potential therapeutic targets to block Tau-mediated pathogenesis.

neuroscience↗

bioRxiv2021

A CRISPRi/a platform in iPSC-derived microglia uncovers regulators of disease states

Microglia are emerging as key drivers of neurological diseases. However, we lack a systematic understanding of the underlying mechanisms. Here, we present a screening platform to systematically elucidate functional consequences of genetic perturbations in human iPSC-derived microglia. We developed an efficient eight-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. We established inducible CRISPR interference and activation in this system and conducted three screens targeting the "druggable genome". These screens uncovered genes controlling microglia survival, activation and phagocytosis, including neurodegeneration-associated genes. A screen with single-cell RNA sequencing as the readout revealed that these microglia adopt a spectrum of states mirroring those observed in human brains and identified regulators of these states. A disease-associated state characterized by SPP1 expression was selectively depleted by CSF1R inhibition. Thus, our platform can systematically uncover regulators of microglia states, enabling their functional characterization and therapeutic targeting.

neuroscience↗

bioRxiv2021

Heterogeneous non-canonical nucleosomes predominate in yeast cells in situ

Nuclear processes depend on the organization of chromatin, whose basic units are cylinder-shaped complexes called nucleosomes. A subset of mammalian nucleosomes in situ (inside cells) resembles the canonical structure determined in vitro 25 years ago. Nucleosome structure in situ is otherwise poorly understood. Using cryo-ET and 3-D classification analysis of budding yeast cells, here we find that canonical nucleosomes account for less than 10% of total nucleosomes expected in situ. In a strain in which H2A-GFP is the sole source of histone H2A, class averages that resemble canonical nucleosomes both with and without GFP densities are found ex vivo (in nuclear lysates), but not in situ. These data suggest that the budding yeast intranuclear environment favors multiple non-canonical nucleosome conformations. Using the structural observations here and the results of previous genomics and biochemical studies, we propose a model in which the average budding yeast nucleosomes DNA is partially detached in situ.

cell biology↗

bioRxiv2021

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy

Activation of microglia, the brains innate immune cells, is a prominent pathological feature in tauopathies, including Alzheimers disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-{kappa}B exacerbated, while inactivation diminished, tau seeding and spreading in PS19 mice, consistent with the observation that NF-{kappa}B activation accelerates processing of internalized tau fibrils in primary microglia. Remarkably, inhibition of microglial NF-{kappa}B specifically also rescued tau-mediated learning and memory deficits, and restored overall transcriptomic changes while increasing tau inclusions. On a single cell level, we discovered that tau-associated disease states in microglia were diminished by NF-{kappa}B inactivation and further transformed by constitutive NF-{kappa}B activation. Our study establishes a central role for microglial NF-{kappa}B signaling in mediating tau toxicity in tauopathy.

neuroscience↗

bioRxiv2021

Caspase inhibition mitigates tau cleavage and neurotoxicity in iPSC-induced neurons with the V337M MAPT mutation

Tau post-translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimers disease (AD). Proteolytic cleavage of tau by active caspases, including caspase-6, represents an underexplored tau PTM implicated in tau pathology. Caspase-cleaved tau is toxic and prone to self-aggregation in experimental models. To elucidate the presence and temporal course of caspase activation, tau cleavage, and neuronal death, we generated two neoepitope monoclonal antibodies (mAbs) against caspase-6 tau proteolytic sites and cortical neurons from induced pluripotent stem cells (iPSCs) with the frontotemporal dementia (FTD)-causing V337M MAPT mutation. FTLD V337M MAPT and AD postmortem brains showed positivity for both cleaved tau mAbs as well as active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons showed a time-dependent increase in pathogenic tau in the form of tau oligomers, caspase-cleaved tau, and p-tau. Accumulation of toxic tau species in 3-month V337M MAPT neurons also increased vulnerability to stress, which was pharmacologically rescued by caspase inhibition. We propose a model in which time-dependent accumulation of caspase-cleaved tau in V337M MAPT neurons promotes neurotoxicity that is reversed by caspase-6 inhibition. Caspase-cleaved tau may be a biomarker of tauopathy, and caspases could be viable targets for therapeutic intervention against tau pathogenesis in FTLD and other tauopathies. SignificanceThe mechanisms leading to tau pathology in frontotemporal dementia (FTD) and Alzheimers disease (AD) remain elusive. Experimental studies in AD demonstrate that tau cleavage by active caspase-6 contributes to tau pathology since cleaved tau may be toxic and prone to self-aggregation. Yet, the role of caspase-cleaved tau in promoting toxicity and cell death is unclear. Here, we generated two neoepitope monoclonal antibodies against caspase-6 tau and evaluated tau cleavage in postmortem human brains, iPSC-induced cortical neurons with the FTD-causing V337M MAPT mutation, and isogenic wild-type MAPT controls. Our results demonstrate a time-dependent accumulation of caspase-cleaved tau and increased neurotoxicity in the mutant iNs that is reversed by caspase-6 inhibition. Caspases could be viable therapeutic targets against tau pathology in tauopathies.

neuroscience↗