Mouse Model Of Disease Research Articles

Neuroprotective Effect of Echinoside on MPTP-induced Parkinson's Disease Mouse Model by Activation of NRF2/HO-1 Pathway

Echinacoside, a principal active compound derived from Cistanche deserticola Ma, is recognized in traditional Chinese medicine for its anti-aging, immunomodulatory, endocrine-regulating, and neuroprotective properties. However, the specific neuroprotective mechanisms of echinacoside remain largely unclear. This study aims to investigate whether the neuroprotective effects of echinacoside in a mouse model of Parkinson's disease (PD) are mediated through the Nrf2/HO-1 signaling pathway by mitigating inflammatory responses.Mice were divided into four groups: control, model, positive control, and echinacoside-treated groups. PD mouse model was induced through intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over the course of one week, followed by three weeks of oral administration of echinacoside. The results demonstrated that echinacoside significantly improved motor function impairments caused by MPTP in PD mice. Immunohistochemical analysis revealed that echinacoside enhanced the expression of tyrosine hydroxylase in the substantia nigra of PD mice. Furthermore, assays of inflammatory cytokines indicated that echinacoside effectively reduced the levels of IL-6 and TNF-α in brain tissues.Western blot analysis further confirmed that echinacoside intervention upregulated the expression of Nrf2 and HO-1 in the brain tissues of PD mice. These findings suggest that echinacoside exerts neuroprotective effects in the PD mouse model, likely through the activation of the Nrf2/HO-1 signaling pathway. Therefore, echinacoside may be considered a potential therapeutic strategy for the treatment of PD.

Gastrodin reduces Aβ brain levels in an Alzheimer's disease mouse model by inhibiting P-glycoprotein ubiquitination

BackgroundStudies have demonstrated the potential of gastrodin in the treatment of Alzheimer's disease (AD), however, its mechanism of action remains elusive. Currently, the Amyloid-β (Aβ) cascade hypothesis continues to be the prevailing theory regarding AD etiology. The ubiquitination of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) contributes to the accumulation of Aβ in the brain during AD. PurposeTo investigate the mechanism of gastrodin intervention in AD. MethodsThe molecular docking, molecular dynamics simulations, and microscale thermophoresis (MST) were employed to identify the action target of gastrodin. The western blot (WB) was performed to detect the protein expression level, the ubiquitination level of P-gp was determined using co-immunoprecipitation (CO-IP) assay. P-gp transport activity was detected using an NBD-CSA fluorescence assay. Trans-Epithelial Electrical Resistance (TEER) was used to detect cell resistance. Fluorescein-labeled dextran experiments were performed to determine the individual cell permeability. The immunofluorescence (IF) was employed to detect Aβ deposition, the Morris Water Maze test was used to assess behavioral changes in APP/PS1 mice and the levels of Aβ40 and Aβ42 expression were quantified using enzyme-linked immunosorbent assay. ResultsThe FBXO15 was the target of gastrodin-mediated inhibition of P-gp ubiquitination. Gastrodin increased the P-gp expression, cell resistance, and P-gp transport activity of BEND.3 cells upon treatment with Aβ40 through mechanisms involving the reduction of FBXO15 and P-gp binding and the inhibition of P-gp ubiquitination. And gastrodin could effectively improve memory function and increase number of neurons in APP/PS1 mice, reduce the accumulation of Aβ40 and Aβ42, and enhance P-gp expression in a dose-dependent manner. ConclusionAβ40 induces the ubiquitination and proteasomal degradation of BBB P-gp, however, gastrodin inhibits the ubiquitination of P-gp by binding to FBXO15, thereby increasing P-gp protein expression and enhancing its transport function.

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer's disease.

The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer's disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored. We generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL-G-F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background. Bace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL-G-F/wt). Insoluble Aβ1-40 and Aβ1-42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL-G-F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1. Our results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.

Regulation of Colonic Inflammation and Macrophage Homeostasis of IFN-γ-Primed Canine AMSCs in Experimental Colitis in Mice

Mesenchymal stem cells (MSCs) have shown potential in treating immune-mediated diseases due to their immunomodulatory properties, which can be enhanced by priming with inflammatory cytokines like interferon-gamma (IFN-γ). This study evaluates the therapeutic effects of IFN-γ-primed canine adipose tissue-derived MSCs (AMSCs) in a mouse model of inflammatory bowel disease (IBD). Canine AMSCs were primed with 50 ng/mL recombinant canine IFN-γ for 48 h, and the effects were compared to those seen in naïve (unprimed) AMSCs. IBD was induced in mice using dextran sodium sulfate (DSS), and AMSCs were injected intraperitoneally on days 1 and 3. The mice treated with IFN-γ-primed AMSCs showed improved clinical outcomes, including a reduced disease activity index (DAI), less body weight loss, and longer colon length compared to the mice treated with naïve AMSCs. A histological analysis revealed less damage to the intestinal structures and reduced inflammatory cell infiltration. IFN-γ priming led to a shift in the immune cell balance in the gut, decreasing pro-inflammatory macrophages (Ly6Chi) and increasing anti-inflammatory macrophages (Ly6Clo/MHC-IIhi). This was associated with the reduced expression of inflammatory cytokine genes (Il-1β, Il-6, and Il-18) and increased expression of the intestinal stem cell marker Lgr5. These findings suggest that IFN-γ-primed AMSCs offer enhanced therapeutic potential for treating CE in veterinary medicine.

Expression of Concern: L'Episcopo et al., "Plasticity of Subventricular Zone Neuroprogenitors in MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine) Mouse Model of Parkinson's Disease Involves Cross Talk between Inflammatory and Wnt/β-Catenin Signaling Pathways: Functional Consequences for Neuroprotection and Repair".

Expression of Concern: L'Episcopo et al., "Plasticity of Subventricular Zone Neuroprogenitors in MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine) Mouse Model of Parkinson's Disease Involves Cross Talk between Inflammatory and Wnt/β-Catenin Signaling Pathways: Functional Consequences for Neuroprotection and Repair".

Magnolol acts as a neurorestorative agent in an Aβ1‑42‑induced mouse model of Alzheimer's disease

Magnolol acts as a neurorestorative agent in an A_β1‑42‑induced mouse model of Alzheimer's disease

A novel phosphodiesterase 5 inhibitor, RF26, improves memory impairment and ameliorates tau aggregation and neuroinflammation in the P301S tauopathy mouse model of Alzheimer's disease.

Phosphodiesterase-5 (PDE5) inhibitors are primarily used in the treatment of erectile dysfunction and pulmonary hypertension, but have also been reported to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD). This is likely to be through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling by elevating cGMP, a secondary messenger involved in processes of neuroplasticity. In the present study, we evaluated the efficacy of a novel PDE5 inhibitor, RF26, using P301S tauopathy mice model. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, including AD, Frontotemporal dementia (FTD), Supranuclear palsy and others. RF26 successfully targeted NO/cGMP signaling pathway and showed a significant improvement of spatial memory task performance of P301S mice using Morris Water Maze and T-maze. Furthermore, RF26 -treated mice showed a significant reduction of phosphorylated tau load, gliosis and downregulated pro-inflammatory cytokines. The presented data support the efficacy of RF26 as a potent PDE5 inhibitor and calls for further investigation as a potential therapeutic drug for Alzheimer's and other tauopathy related neurological disorders.

ACSL3 is a promising therapeutic target for alleviating anxiety and depression in Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, affects over 55 million people worldwide and is often accompanied by depression and anxiety. Both significantly impact patients' quality of life and impose substantial societal and economic burdens on healthcare systems. Identifying the complex regulatory mechanisms that contribute to the psychological and emotional deficits in AD will provide promising therapeutic targets. Biosynthesis of omega-3 (ω3) and omega-6 fatty acids (ω6-FA) through long-chain acyl-CoA synthetases (ACSL) is crucial for cell function and survival. This is due to ω3/6-FA's imperative role in modulating the plasma membrane, energy production, and inflammation. While ACSL dysfunction is known to cause heart, liver, and kidney diseases, the role of ACSL in pathological conditions in the central nervous system (e.g., depression and anxiety) remains largely unexplored. The impact of ACSLs on AD-related depression and anxiety was investigated in a mouse model of Alzheimer's disease (3xTg-AD). ACSL3 levels were significantly reduced in the hippocampus of aged 3xTg-AD mice (via capillary-based immunoassay). This reduction in ACAL3 was closely associated with increased depression and anxiety-like behavior (via forced swim, tail suspension, elevated plus maze, and sucrose preference test). Upregulation of ACSL3 via adenovirus in aged 3xTg-AD mice led to increased protein levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor C (VEGF-C) (via brain histology, capillary-based immunoassay), resulting in alleviation of depression and anxiety symptoms. The present study highlights a novel neuroprotective role of ACSL3 in the brain. Targeting ACSL3 will offer an innovative approach for treating AD-related depression and anxiety.

A novel chronic obstructive pulmonary disease mouse model induced by intubation-mediated intratracheal co-administration of porcine pancreatic elastase and lipopolysaccharide.

Chronic obstructive pulmonary disease (COPD) is a significant respiratory disorder in humans characterized by persistent airway constriction or obstruction due to chronic bronchitis and pulmonary emphysema. Various methods of inducing COPD in mouse models are frequently used in COPD research; however, these cannot completely reproduce histopathologic lesions. This study aimed to establish a new COPD mouse model that reproduces histopathological lesions closely resembling clinical COPD within a shorter induction time. The new strategy involved the co-administration of porcine pancreatic elastase (PPE) and lipopolysaccharide (LPS), with PPE intended to induce pulmonary emphysema and LPS intended to induce chronic bronchitis. Male C57BL/6J mice were administered PPE (8 U/kg) on days 0 and 3 and LPS (400µg/kg) on days 6, 9, 12, and 15. Each administration was performed using a noninvasive intubation-mediated intratracheal instillation method with a laryngoscope. Postmortem examination on day 22 revealed that pulmonary emphysema and chronic bronchitis were simultaneously induced in 90.91% of the lung lobes. Molecular studies revealed higher messenger ribonucleic acid (mRNA) expression levels of interleukin-6(IL-6) and matrix metalloproteinase-12(MMP-12) associated with the pathogenesis of COPD. A new method was developed to establish a COPD mouse model that displays a more severe representation of the histopathological findings of clinical COPD than previous COPD models. It also reduces the time required for model induction. This newly developed COPD mouse model is expected to be a valuable tool for the pathogenesis and therapeutic research on human COPD.

Establishment and Use of Primary Cultured Astrocytes from Alexander Disease Model Mice

Alexander disease (AxD) is an intractable neurodegenerative disease caused by mutations in glial fibrillary acidic protein (GFAP), which is predominantly expressed in astrocytes. Thus, AxD is a primary astrocyte disease. However, it remains unclear how GFAP mutations affect astrocytes and cause AxD pathology. Three features are characteristic of AxD astrocytes in vivo: (1) Rosenthal fibers (RFs), the hallmark of AxD; (2) aberrant Ca2+ signals (AxCa); and (3) upregulation of disease-associated genes (AxGen). We established a primary culture system for astrocytes from an AxD transgenic mouse model, and used it to analyze the above features of AxD pathogenesis in astrocytes in vitro. We observed the formation of RFs in AxD primary cultures. The abundance of RFs was greater in AxD-transgene-homozygous compared with -hemizygous astrocytes, indicating a gene dosage effect, and this abundance increased with time in culture, indicating a developmental process effect. However, cultured AxD astrocytes did not exhibit changes in either AxCa or AxGen. We therefore conclude that RFs in astrocytes form via a cell-autonomous mechanism, whereas AxCa and AxGen are likely to occur via a non-cell-autonomous mechanism through interactions with other cells, such as neurons, microglia, and vascular cells. Although primary cultured AxD astrocytes are suitable for elucidating the mechanisms of RFs formation and for intervention studies, it should be noted that they cannot reflect the pathophysiology of non-cell-autonomous events in astrocytes.

Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimers disease mouse model.

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to Spastic Paraplegia (HSP), leads to a similar build of lysosomes in structures we term AP-4 dystrophies. Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, beta-site cleaving enzyme 1 (BACE1) and Presenilin 2. Our studies examining whether the abnormal axonal lysosome build up resulting from AP-4 loss could lead to amyloidogenesis revealed that the loss of AP-4 complex function in an Alzheimer disease model resulted in a strong increase in size and abundance of amyloid plaques in the hippocampus and corpus callosum as well as increased microglial association with the plaques. Interestingly, we found a further increase in enrichment of the secretase, BACE1, in the axonal swellings of the plaques of Alzheimer model mice lacking AP-4 complex compared to those having normal AP-4 complex function, suggestive of increased amyloidogenic processing under this condition. Additionally, the exacerbation of plaque pathology was region-specific as it did not increase in the cortex. The burden of the AP-4 linked axonal dystrophies/AP-4 dystrophies was higher in the corpus callosum and hippocampus compared to the cortex, establishing the critical role of AP-4 -dependent axonal lysosome transport and maturation in regulating amyloidogenic amyloid precursor protein processing.

Expression Profiles of Brain-Derived Neurotrophic Factor Splice Variants in the Hippocampus of Alzheimer's Disease Model Mouse.

Dysregulation of brain-derived neurotrophic factor (BDNF) has been implicated in Alzheimer's disease (AD). In this study, we investigated the temporal dynamics of BDNF expression in the hippocampus of 5xFAD mice, an AD model, focusing on sex and age differences and Bdnf mRNA splice variants. At 3 months of age, female wild-type (WT) mice exhibited significantly higher Bdnf mRNA levels compared to males. However, this difference was abolished in female 5xFAD mice. At 6 months of age, no sex differences in Bdnf mRNA levels were observed in WT mice, and the levels tended to be lower in female 5xFAD mice. Additionally, a significant decrease in the mRNA levels of full-length tropomyosin-related kinase B (TrkB), a BDNF receptor, was found in female 5xFAD mice at 6 months, while mRNA levels of the truncated TrkB were increased in both male and female 5xFAD mice. Specifically, among the Bdnf mRNA splice variants, the levels of Bdnf exon IIA-IX, exon IIB-IX, exon IIC-IX, and exon IXA mRNA were significantly higher in female WT mice compared to male WT mice at 3 months, but this difference was lost in female 5xFAD mice. These findings suggest that the expression of specific Bdnf splice variants would be maintained at higher levels in the hippocampus of young female mice than in males but may be disrupted in AD model mice. Our study may provide insights into the relationship between sex differences in AD onset and BDNF expression.

Metabolomics reveals the metabolic disturbance caused by arsenic in the mouse model of inflammatory bowel disease

Arsenic exposure has long been a significant global health concern due to its association with various human diseases. The adverse health effects of arsenic can be influenced by multiple factors, resulting in considerable individual variability. Individuals with inflammatory bowel disease (IBD) are particularly vulnerable to the effects of toxin exposure, yet the specific impact of arsenic in the context of IBD remains unclear. In this study, we employed a non-targeted metabolomics approach to investigate how arsenic exposure affects metabolic homeostasis in an IBD model using Helicobacter trogontum-infected interleukin-10 deficient mice. Our results demonstrated that arsenic exposure disrupted the balance of various metabolites, including tryptophan, polyunsaturated fatty acids, purine and pyrimidine metabolites, and branched-chain amino acids, in mice with colitis but not in those without colitis. Notably, several crucial metabolites involved in anti-inflammatory responses, oxidative stress, and energy metabolism were significantly altered in mice with colitis. These results indicate that arsenic exposure in an IBD context can lead to extensive metabolic disturbances, potentially exacerbating disease severity and impacting overall health. This study underscores the necessity of evaluating arsenic toxicity in relation to IBD to better understand and mitigate associated health risks.

Abnormally accumulated GM2 ganglioside contributes to skeletal deformity in Tay-Sachs mice.

Tay-Sachs Disease is a rare lysosomal storage disorder caused by mutations in the HEXA gene, responsible for the degradation of ganglioside GM2. In addition to progressive neurodegeneration, Tay-Sachs patients display bone anomalies, including kyphosis. Tay-Sachs disease mouse model (Hexa-/-Neu3-/-) shows both neuropathological and clinical abnormalities of the infantile-onset disease phenotype. In this study, we investigated the effects of GM2 accumulation on bone remodeling activity. Here, we evaluated the bone phenotype of 5-month-old Hexa-/-Neu3-/- mice with age-matched control groups using gene expression analysis, bone plasma biomarker analysis, and micro-computed tomography. We demonstrated lower plasma alkaline phosphatase activity and calcium levels with increased tartrate-resistant acid phosphatase levels, indicating reduced bone remodeling activity in mice. Consistently, gene expression analysis confirmed osteoblast reduction and osteoclast induction in the femur of mice. Micro-computed tomography and analysis show reduced trabecular bone volume, mineral density, number, and thickness in Hexa-/-Neu3-/- mice. In conclusion, we demonstrated that abnormal GM2 ganglioside accumulation significantly triggers skeletal abnormality in Tay-Sachs mice. We suggest that further investigation of the molecular basis of bone structure anomalies is necessary to elucidate new therapeutic targets that preventthe progression ofbone symptoms and improve the life standards of Tay-Sachs patients. KEY MESSAGES: We detected the markers of bone loss-associated disorders such as osteopenia and osteoporosis in the Tay-Sachs disease mice model Hexa-/-Neu3-/-. We also demonstrated for the first time there is an increase in trabecular spacing and a reduction in trabecular thickness and number indicating skeletal abnormalities in mice model using micro-CT analysis.

Deletion of Gba in neurons, but not microglia, causes neurodegeneration in a Gaucher mouse model.

Gaucher disease, the most prevalent lysosomal storage disease, is caused by homozygous mutations at the GBA gene, which is responsible for encoding the enzyme glucocerebrosidase. Neuronopathic Gaucher disease is associated with microgliosis, astrogliosis, and neurodegeneration. However, the role that microglia, astrocytes, and neurons play in the disease remains to be determined. In the current study, we developed inducible, cell-type-specific Gba-KO mice to better understand the individual impacts of Gba deficiencies on microglia and neurons. Gba was conditionally knocked out either exclusively in microglia or neurons or throughout the body. These mouse models were developed using a tamoxifen-inducible Cre system, with tamoxifen administration commencing at weaning. Microglia-specific Gba-KO mice showed no signs of disease. However, the neuron-specific Gba KO resulted in a shortened lifespan, severe weight loss, and ataxia. These mice also had significant neurodegeneration, microgliosis, and astrogliosis accompanied by the accumulation of glucosylceramide and glucosylsphingosine, recapitulating Gaucher disease-like symptoms. These surprising findings reveal that, unlike the neuron-specific Gba deficiency, microglia-specific Gba deficiency alone does not induce disease. The neuronal Gaucher disease mouse model, with a median survival of 16 weeks, may be useful for future studies of pathogenesis and the evaluation of therapies.

Contribution of gut microbiota to the development of Crohn's disease: Insights gained from fecal microbiota transplantation studies in mice.

We would like to present some new thoughts on the publication in the journal published in August 2024 in World Journal of Gastroenterology. We specifically focused on the alterations in the intestinal tract, mesenteric adipose tissue (MAT), and systemic inflammatory changes in mice following fecal flora transplantation into a mouse model of Crohn's disease (CD). Accumulating evidence suggests that the occurrence of CD is influenced by environmental factors, host immune status, genetic susceptibility, and flora imbalance. One microbiota-based intervention, fecal microbiota transplantation, has emerged as a potential treatment option for CD. The MAT is considered a "second barrier" around the inflamed intestine. The interaction between gut microbes and inflammatory changes in MAT has attracted considerable interest. In the study under discussion, the authors transplanted fetal fecal microorganisms from patients with CD and clinically healthy donors, respectively, into 2,4,6-trinitrobenzene sulfonic acid-induced CD mice. The research explored the complex interplay between MAT, creeping fat, inflammation, and intestinal flora in CD by evaluating intestinal and mesenteric lesions, along with the systemic inflammatory state in the mice. This article provides several important insights. First, the transplantation of intestinal flora holds significant potential as a therapeutic strategy for CD, offering hope for patients with CD. Second, it presents a novel approach to the diagnosis and treatment of CD: The inflammatory response in CD could potentially be assessed through pathological or imaging changes in the MAT, and CD could be treated by targeting the inflammation of the MAT.

Investigation of the therapeutic effects and mechanisms of Houpo Mahuang Decoction on a mouse model of chronic obstructive pulmonary disease

Investigation of the therapeutic effects and mechanisms of Houpo Mahuang Decoction on a mouse model of chronic obstructive pulmonary disease

Molecular basis of neurodegeneration in a mouse model of Polr3-related disease

Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of Polr3-related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of Polr3-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic Polr3a mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, cerebral pathology and exocrine pancreatic atrophy. Transcriptome and immunohistochemistry analyses of cerebra during disease progression show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell-type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. Earlier in the disease when integrated stress and innate immune responses are minimally induced, mature tRNA sequencing revealed a global reduction in tRNA levels and an altered tRNA profile but no changes in other Pol III transcripts. Thus, changes in the size and/or composition of the tRNA pool have a causal role in disease initiation. Our findings reveal different tissue- and brain region-specific sensitivities to a defect in Pol III transcription.

Molecular basis of neurodegeneration in a mouse model of Polr3-related disease.

Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of Polr3-related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of Polr3-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic Polr3a mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, cerebral pathology and exocrine pancreatic atrophy. Transcriptome and immunohistochemistry analyses of cerebra during disease progression show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell-type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. Earlier in the disease when integrated stress and innate immune responses are minimally induced, mature tRNA sequencing revealed a global reduction in tRNA levels and an altered tRNA profile but no changes in other Pol III transcripts. Thus, changes in the size and/or composition of the tRNA pool have a causal role in disease initiation. Our findings reveal different tissue- and brain region-specific sensitivities to a defect in Pol III transcription.

Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.

The transmission of tau pathology has been proposed as one of the major mechanisms for the spatiotemporal spreading of tau pathology in neurodegenerative diseases. Over the last decade, studies have demonstrated that targeting total or pathological tau using tau antibodies can mitigate the development of tau pathology in tauopathy or Alzheimer's disease (AD) mouse models, and multiple tau immunotherapy agents have progressed to clinical trials. Tau antibodies are believed to inhibit the internalization of pathologic seeds and/or block seed elongation after seed internalization. To further address the mechanism of tau antibody inhibition of pathological spread, we conducted immunotherapy studies in mouse primary neurons and wild-type mice (females) seeded with AD patient-derived tau to induce the formation and spreading of tau pathology. Notably, we evaluated the effect of a mouse tau-specific antibody (mTau8) which does not interact with AD-tau seeds in these models. Our results show that mTau8 crosses the blood-brain barrier at levels similar to other antibodies and effectively decreases AD-tau-seeded tau pathology in vitro and in vivo. Importantly, our data suggest that mTau8 binds to endogenous intraneuronal mouse tau, thereby inhibiting the elongation of internalized tau seeds. These findings provide valuable insights into the possible mechanism underlying antibody-based therapies for treating tauopathies.Significance Statement The transmission of tau pathology plays key role in the pathoclinical progression of tauopathy. Studies have shown that tau antibody treatment can mitigate tau pathology in transgenic and spreading models of tauopathy. To explore the mechanisms involved in this procedure, we conducted immunotherapy studies on human tau seeds induced tau spreading models using a mouse tau-specific antibody (mTau8), which does not interact with human-tau seeds. Our findings in the study enhance our understanding of antibody-based therapies for tauopathies.