RESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which changes in hearing sensitivity precede cognitive decline. Despite a well-known link between dementia and hearing loss, few AD model mouse lines have hearing characterized. We screened for hearing loss using auditory brainstem responses (ABR) in young (3-4 months) and aging (9-10 months) mice with a P301S tauopathy (PS19 mice). Compared to wild types, aging PS19 mice did not show accelerated hearing loss but did show latency differences in centrally generated ABR waveform components. These results suggest that tauopathy causes mild central auditory dysfunction in the absence of overt hearing loss.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico , Tauopatias , Animais , Doença de Alzheimer/fisiopatologia , Camundongos , Tauopatias/fisiopatologia , Tauopatias/patologia , Camundongos Transgênicos , Perda Auditiva/fisiopatologia , Perda Auditiva/etiologia , Humanos , Audiometria/métodosRESUMO
BACKGROUND AND OBJECTIVES: Anti-IgLON5 disease is an autoimmune neurodegenerative disorder characterized by various phenotypes, notably sleep and movement disorders and tau pathology. Although the disease is known to be associated with the neuronal cell adhesion protein IgLON5, the physiologic function of IgLON5 remains elusive. There are conflicting views on whether autoantibodies cause loss of function, activation of IgLON5, or inflammation-associated neuronal damage, ultimately leading to the disease. We generated IgLON5 knockout (-/-) mice to investigate the functions of IgLON5 and elucidate the pathomechanism of anti-IgLON5 disease. METHODS: IgLON5 knockout (-/-) mice underwent behavioral tests investigating motor function, psychiatric function (notably anxiety and depression), social and exploratory behaviors, spatial learning and memory, and sensory perception. Histologic analysis was conducted to investigate tau aggregation in mice with tauopathy. RESULTS: IgLON5-/- mice had poorer performance in the wire hang and rotarod tests (which are tests for motor function) than wild-type mice. Moreover, IgLON5-/- mice exhibited decreased anxiety-like behavior and/or hyperactivity in behavior tests, including light/dark transition test and open field test. IgLON5-/- mice also exhibited poorer remote memory in the contextual fear conditioning test. However, neither sleeping disabilities assessed by EEG nor tau aggregation was detected in the knockout mice. DISCUSSION: These results suggest that IgLON5 is associated with activity, anxiety, motor ability, and contextual fear memory. Comparing the various phenotypes of anti-IgLON5 disease, anti-IgLON5 disease might partially be associated with loss of function of IgLON5; however, other phenotypes, such as sleep disorders and tau aggregation, can be caused by gain of function of IgLON5 and/or neuronal damage due to inflammation. Further studies are needed to elucidate the role of IgLON5 in the pathogenesis of anti-IgLON5 diseases.
Assuntos
Moléculas de Adesão Celular Neuronais , Camundongos Knockout , Fenótipo , Animais , Masculino , Camundongos , Ansiedade/imunologia , Autoanticorpos/sangue , Comportamento Animal/fisiologia , Moléculas de Adesão Celular Neuronais/deficiência , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Tauopatias/fisiopatologia , Tauopatias/imunologia , HumanosRESUMO
Tumor progression locus 2 (TPL2) (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNA sequencing analysis indicates that protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS (inducible nitric oxide synthase) induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.
Assuntos
MAP Quinase Quinase Quinases , Tauopatias , Animais , Humanos , Camundongos , Encéfalo/patologia , Células Cultivadas , Espinhas Dendríticas/patologia , Lipopolissacarídeos , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Camundongos Knockout , Microglia/metabolismo , Doenças Neuroinflamatórias/patologia , Análise de Sequência de RNA , Análise de Célula Única , Proteínas tau/genética , Proteínas tau/metabolismo , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/fisiopatologiaRESUMO
BACKGROUND: Bradykinesia is a cardinal feature in parkinsonisms. No study has assessed the differential features of bradykinesia in patients with pathology-proven synucleinopathies and tauopathies. OBJECTIVE: We examined whether bradykinesia features (speed, amplitude, rhythm, and sequence effect) may differ between pathology-proven synucleinopathies and tauopathies. METHODS: Forty-two cases who underwent autopsy were included and divided into synucleinopathies (Parkinson's disease and dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy). Two raters blinded to the diagnosis retrospectively scored the Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and Modified Bradykinesia Rating Scale on standardized videotaped neurological examinations. Bradykinesia scores were compared using the Mann-Whitney test and logistic regression models to adjust for disease duration. RESULTS: Demographic and clinical parameters were similar between synucleinopathies and tauopathies. There were no differences between speed, amplitude, rhythm, and sequence effect in synucleinopathies and tauopathies in unadjusted comparisons and adjusted models (all P > 0.05). CONCLUSIONS: Clinical bradykinesia features do not distinguish the underlying neuropathology in neurodegenerative parkinsonisms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Hipocinesia , Doença de Parkinson , Sinucleinopatias , Tauopatias , Gravação em Vídeo , Humanos , Hipocinesia/complicações , Hipocinesia/fisiopatologia , Modelos Logísticos , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Estudos Retrospectivos , Estatísticas não Paramétricas , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/fisiopatologia , Sinucleinopatias/complicações , Sinucleinopatias/patologia , Sinucleinopatias/fisiopatologia , Tauopatias/complicações , Tauopatias/patologia , Tauopatias/fisiopatologia , Autopsia , Masculino , Feminino , Pessoa de Meia-Idade , IdosoRESUMO
Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer's disease (AD). Apolipoprotein E4 (APOE4), the highest genetic risk factor for late-onset AD, has been shown to exacerbate tau hyperphosphorylation in mouse models. However, the exact mechanisms through which APOE4 induces tau hyperphosphorylation remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), which we identify as a binding partner of APOE4, drives tau hyperphosphorylation. We discovered that first, GPC-4 preferentially interacts with APOE4 in comparison to APOE2, considered to be a protective allele to AD, and second, that postmortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. Furthermore, the astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9-mediated activation of GPC-4 in a tauopathy mouse model robustly induced tau hyperphosphorylation. In the absence of GPC4, APOE4-induced tau hyperphosphorylation was largely diminished using in vitro tau fluorescence resonance energy transfer-biosensor cells, in human-induced pluripotent stem cell-derived astrocytes and in an in vivo mouse model. We further show that APOE4-mediated surface trafficking of APOE receptor low-density lipoprotein receptor-related protein 1 through GPC-4 can be a gateway to tau spreading. Collectively, these data support that APOE4-induced tau hyperphosphorylation is directly mediated by GPC-4.
Assuntos
Doença de Alzheimer , Astrócitos , Glipicanas , Proteínas tau , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E2/genética , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Astrócitos/metabolismo , Modelos Animais de Doenças , Glipicanas/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Fosforilação , Tauopatias/metabolismo , Tauopatias/fisiopatologia , Proteínas tau/metabolismoRESUMO
Tau assembly movement from the extracellular to intracellular space may underlie transcellular propagation of neurodegenerative tauopathies. This begins with tau binding to cell surface heparan sulfate proteoglycans, which triggers macropinocytosis. Pathological tau assemblies are proposed then to exit the vesicular compartment as "seeds" for replication in the cytoplasm. Tau uptake is highly efficient, but only â¼1 to 10% of cells that endocytose aggregates exhibit seeding. Consequently, we studied fluorescently tagged full-length (FL) tau fibrils added to native U2OS cells or "biosensor" cells expressing FL tau or repeat domain. FL tau fibrils bound tubulin. Seeds triggered its aggregation in multiple locations simultaneously in the cytoplasm, generally independent of visible exogenous aggregates. Most exogenous tau trafficked to the lysosome, but fluorescence imaging revealed a small percentage that steadily accumulated in the cytosol. Intracellular expression of Gal3-mRuby, which binds intravesicular galactosides and forms puncta upon vesicle rupture, revealed no evidence of vesicle damage following tau exposure, and most seeded cells had no evidence of endolysosome rupture. However, live-cell imaging indicated that cells with pre-existing Gal3-positive puncta were seeded at a slightly higher rate than the general population, suggesting a potential predisposing role for vesicle instability. Clearance of tau seeds occurred rapidly in both vesicular and cytosolic fractions. The lysosome/autophagy inhibitor bafilomycin inhibited vesicular clearance, whereas the proteasome inhibitor MG132 inhibited cytosolic clearance. Tau seeds that enter the cell thus have at least two fates: lysosomal clearance that degrades most tau, and entry into the cytosol, where seeds amplify, and are cleared by the proteasome.
Assuntos
Citosol , Lisossomos , Tauopatias , Proteínas tau , Doença de Alzheimer/fisiopatologia , Citosol/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Humanos , Lisossomos/metabolismo , Tauopatias/metabolismo , Tauopatias/fisiopatologia , Proteínas tau/metabolismoRESUMO
Ubiquitin-modified tau aggregates are abundantly found in human brains diagnosed with Alzheimer's disease (AD) and other tauopathies. Soluble tau oligomers (TauO) are the most neurotoxic tau species that propagate pathology and elicit cognitive deficits, but whether ubiquitination contributes to tau formation and spreading is not fully understood. Here, we observed that K63-linked, but not K48-linked, ubiquitinated TauO accumulated at higher levels in AD brains compared with age-matched controls. Using mass spectrometry analyses, we identified 11 ubiquitinated sites on AD brain-derived TauO (AD TauO). We found that K63-linked TauO are associated with enhanced seeding activity and propagation in human tau-expressing primary neuronal and tau biosensor cells. Additionally, exposure of tau-inducible HEK cells to AD TauO with different ubiquitin linkages (wild type, K48, and K63) resulted in enhanced formation and secretion of K63-linked TauO, which was associated with impaired proteasome and lysosome functions. Multipathway analysis also revealed the involvement of K63-linked TauO in cell survival pathways, which are impaired in AD. Collectively, our study highlights the significance of selective TauO ubiquitination, which could influence tau aggregation, accumulation, and subsequent pathological propagation. The insights gained from this study hold great promise for targeted therapeutic intervention in AD and related tauopathies.
Assuntos
Doença de Alzheimer , Ubiquitinação , Proteínas tau , Doença de Alzheimer/fisiopatologia , Células Cultivadas , Humanos , Lisina/metabolismo , Neurônios/patologia , Tauopatias/fisiopatologia , Ubiquitina/metabolismo , Proteínas tau/metabolismoRESUMO
Tauopathy is a term that has been used to represent a pathological condition in which hyperphosphorylated tau protein aggregates in neurons and glia which results in neurodegeneration, synapse loss and dysfunction and cognitive impairments. Recently, drug repositioning strategy (DRS) becomes a promising field and an alternative approach to advancing new treatments from actually developed and FDA approved drugs for an indication other than the indication it was originally intended for. This paradigm provides an advantage because the safety of the candidate compound has already been established, which abolishes the need for further preclinical safety testing and thus substantially reduces the time and cost involved in progressing of clinical trials. In the present review, we focused on correlation between tauopathy and common diseases as type 2 diabetes mellitus and the global virus COVID-19 and how tau pathology can aggravate development of these diseases in addition to how these diseases can be a risk factor for development of tauopathy. Moreover, correlation between COVID-19 and type 2 diabetes mellitus was also discussed. Therefore, repositioning of a drug in the daily clinical practice of patients to manage or prevent two or more diseases at the same time with lower side effects and drug-drug interactions is a promising idea. This review concluded the results of pre-clinical and clinical studies applied on antidiabetics, COVID-19 medications, antihypertensives, antidepressants and cholesterol lowering drugs for possible drug repositioning for management of tauopathy.
Assuntos
Antivirais/farmacologia , COVID-19/fisiopatologia , Reposicionamento de Medicamentos , Hipoglicemiantes/farmacologia , Tauopatias/tratamento farmacológico , Antidepressivos/farmacologia , Anti-Hipertensivos/farmacologia , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 2/fisiopatologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Terapia de Alvo Molecular/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tauopatias/fisiopatologia , Tratamento Farmacológico da COVID-19RESUMO
Pathological aggregation of tau and neuroinflammatory changes mark the clinical course of Alzheimer's disease and related tauopathies. To understand the correlation between these pathological hallmarks and functional deficits, we assessed behavioral and physiological deficits in the PS19 mouse model, a broadly utilized model of tauopathy. At 9 months, PS19 mice have characteristic hyperactive behavior, a decline in motor strength, and deterioration in physiological conditions marked by lower body temperature, reduced body weight, and an increase in measures of frailty. Correlation of these deficits with different pathological hallmarks revealed that pathological tau species, characterized by soluble p-tau species, and tau seeding bioactivity correlated with impairment in grip strength and thermal regulation. On the other hand, astrocyte reactivity showed a positive correlation with the hyperactive behavior of the PS19 mice. These results suggest that a diverse spectrum of soluble pathological tau species could be responsible for different symptoms and that neuroinflammation could contribute to functional deficits independently from tau pathology. These observations enhance the necessity of a multi-targeted approach for the treatment of neurodegenerative tauopathies.
Assuntos
Gliose/etiologia , Doenças Neuroinflamatórias/complicações , Agregação Patológica de Proteínas/complicações , Tauopatias/etiologia , Proteínas tau/metabolismo , Animais , Comportamento Animal , Regulação da Temperatura Corporal , Modelos Animais de Doenças , Feminino , Fragilidade/etiologia , Força da Mão , Humanos , Masculino , Camundongos Transgênicos , Atividade Motora , Tauopatias/patologia , Tauopatias/fisiopatologia , Tauopatias/psicologiaRESUMO
Tauopathies are a group of progressive neurodegenerative disorders characterized by the presence of insoluble intracellular tau filaments in the brain. Evidence suggests that there is a tight connection between mitochondrial dysfunction and tauopathies, including Alzheimer's disease. However, whether mitochondrial dysfunction occurs prior to the detection of tau aggregates in tauopathies remains elusive. Here, we utilized transgenic nematodes expressing the full length of wild type tau in neuronal cells and monitored mitochondrial morphology alterations over time. Although tau-expressing nematodes did not accumulate detectable levels of tau aggregates during larval stages, they displayed increased mitochondrial damage and locomotion defects compared to the control worms. Chelating calcium restored mitochondrial activity and improved motility in the tau-expressing larvae suggesting a link between mitochondrial damage, calcium homeostasis and neuronal impairment in these animals. Our findings suggest that defective mitochondrial function is an early pathogenic event of tauopathies, taking place before tau aggregation and undermining neuronal homeostasis and organismal fitness. Understanding the molecular mechanisms causing mitochondrial dysfunction early in tauopathy will be of significant clinical and therapeutic value and merits further investigation.
Assuntos
Homeostase/fisiologia , Mitocôndrias , Tauopatias , Proteínas tau/metabolismo , Doença de Alzheimer , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Modelos Animais de Doenças , Humanos , Larva/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Tauopatias/metabolismo , Tauopatias/fisiopatologiaRESUMO
Tauopathies refer to a group of neurodegenerative diseases with intracellular accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) in neurons and glial cells. PS19 mice bearing the MAPT P301S mutation have been used to mimic human frontotemporal lobar degeneration. The present study was designed to systematically investigate how behavioural functions, resting cerebral blood flow (CBF) and tau pathology change in PS19 mice at 2, 4, 6, 8 and 12 months of age in a single study under one experimental condition, allowing for the cumulative assessment of age- and genotype-dependent changes. PS19 mice displayed hyperactivity and reduced anxiety levels with age, early and persistent spatial working memory deficits and reduced resting neocortical CBF. Immunoblotting and immunohistochemistry revealed age-related increases in phosphorylated tau in the brain of PS19 mice. In conclusion, the present study, for the first time, cumulatively demonstrated the time-course of changes in behavioural functions, resting CBF and tau pathology in a P301S tauopathy mouse model through their developmental span. This information provides further evidence for the utility of this model to study neurodegenerative events associated with tauopathy and tau dysfunction.
Assuntos
Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/metabolismo , Circulação Cerebrovascular , Mutação , Tauopatias/etiologia , Tauopatias/fisiopatologia , Proteínas tau/genética , Alelos , Substituição de Aminoácidos , Animais , Comportamento Animal , Peso Corporal , Córtex Cerebral/patologia , Modelos Animais de Doenças , Aprendizagem , Aprendizagem em Labirinto , Memória , Camundongos , Neuroglia/metabolismo , Neurônios/metabolismo , Tauopatias/metabolismo , Tauopatias/patologia , Proteínas tau/metabolismoRESUMO
Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD-like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5-7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies.
Assuntos
Doença de Alzheimer/genética , Transtornos Cognitivos/genética , Epigenômica/métodos , Emaranhados Neurofibrilares/metabolismo , Tauopatias/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/patologiaRESUMO
Tauopathy refers to a group of progressive neurodegenerative diseases, including frontotemporal lobar degeneration and Alzheimer's disease, which correlate with the malfunction of microtubule-associated protein Tau (MAPT) due to abnormal hyperphosphorylation, leading to the formation of intracellular aggregates in the brain. Despite extensive efforts to understand tauopathy and develop an efficient therapy, our knowledge is still far from complete. To find a solution for this group of devastating diseases, several animal models that mimic diverse disease phenotypes of tauopathy have been developed. Rodents are the dominating tauopathy models because of their similarity to humans and established disease lines, as well as experimental approaches. However, powerful genetic animal models using Drosophila, zebrafish, and C. elegans have also been developed for modeling tauopathy and have contributed to understanding the pathophysiology of tauopathy. The success of these models stems from the short lifespans, versatile genetic tools, real-time in-vivo imaging, low maintenance costs, and the capability for high-throughput screening. In this review, we summarize the main findings on mechanisms of tauopathy and discuss the current tauopathy models of these non-rodent genetic animals, highlighting their key advantages and limitations in tauopathy research.
Assuntos
Modelos Animais de Doenças , Tauopatias/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Drosophila/genética , Drosophila/fisiologia , Humanos , Tauopatias/fisiopatologia , Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Proteínas tau/genéticaRESUMO
Introduction: O-GlcNAcylation is a highly abundant post-translational modification of multiple proteins, including the microtubule-binding protein tau, governed by just two enzymes' concerted action O-GlcNAc transferase OGT and the hydrolase OGA. It is an approach to reduce abnormal tau hyperphosphorylation and aggregation in Alzheimer's disease (AD) and related tauopathies based on the ability of O-GlcNAcylation competing with tau phosphorylation, thus minimizing aggregation. The preclinical validation confirmed OGA inhibitors' efficacy in different transgenic tau mice models. Only three other OGA inhibitors have advanced into clinical trials thus far.Areas covered: 2008-2020 patent literature on OGA inhibitors.Expert opinion: Neurodegenerative disorders and AD specifically represent an enormous challenge since no effective treatments are available. Promising preclinical data has prompted considerable interest in searching for OGA inhibitors as a potential treatment for neurodegenerative disorders. Efforts from different companies have yielded a diverse set of chemotypes. OGA is a highly ubiquitous enzyme with many client proteins, generated data confirms a promising benign profile for OGA inhibition in healthy volunteers. Additionally, OGA PET tracers' existence will be critical for proper dose selection for future PoC Phase II studies, which will proof the true potential of OGA inhibition for the treatment of AD and other tauopathies.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Tauopatias/tratamento farmacológico , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Doença de Alzheimer/fisiopatologia , Animais , Humanos , Camundongos , Patentes como Assunto , Fosforilação , Processamento de Proteína Pós-Traducional , Tauopatias/fisiopatologia , beta-N-Acetil-Hexosaminidases/metabolismo , Proteínas tau/metabolismoRESUMO
Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein tau (MAPT), which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in MAPT pre-mRNA produces equal amounts of protein isoforms with either three (3R) or four (4R) microtubule binding domains. Imbalance in the 3R:4R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal. Here we report motor coordination impairments in the htau mouse model of tauopathy which harbour abnormal 3R:4R tau isoforms content, and in contrast to TauKO mice, are unresponsive to l-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses indicated the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results suggest that abnormal striatal tau isoform content might lead to parkinsonian-like phenotypes and demonstrate a proof of concept that modulation of tau mis-splicing is a plausible disease-modifying therapy for some primary tauopathies.
Assuntos
Corpo Estriado/metabolismo , Transtornos Motores/metabolismo , Destreza Motora/fisiologia , Tauopatias/metabolismo , Proteínas tau/metabolismo , Processamento Alternativo , Animais , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Transtornos Motores/genética , Transtornos Motores/fisiopatologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Tauopatias/genética , Tauopatias/fisiopatologia , Proteínas tau/genéticaRESUMO
The microtubule-associated protein tau promotes the stabilization of the axonal cytoskeleton in neurons. In several neurodegenerative diseases, such as Alzheimer's disease, tau has been found to dissociate from microtubules, leading to the formation of pathological aggregates that display an amyloid fibril-like structure. Recent structural studies have shown that the tau filaments isolated from different neurodegenerative disorders have structurally distinct fibril cores that are specific to the disease. These "strains" of tau fibrils appear to propagate between neurons in a prion-like fashion that maintains their initial template structure. In addition, the strains isolated from diseased tissue appear to have structures that are different from those made by the most commonly used in vitro modeling inducer molecule, heparin. The structural differences among strains in different diseases and in vitro-induced tau fibrils may contribute to recent failures in clinical trials of compounds designed to target tau pathology. This study identifies an isoquinoline compound (ANTC-15) isolated from the fungus Aspergillus nidulans that can both inhibit filaments induced by arachidonic acid (ARA) and disassemble preformed ARA fibrils. When compared to a tau aggregation inhibitor currently in clinical trials (LMTX, LMTM, or TRx0237), ANTC-15 and LMTX were found to have opposing inducer-specific activities against ARA and heparin in vitro-induced tau filaments. These findings may help explain the disappointing results in translating potent preclinical inhibitor candidates to successful clinical treatments.
Assuntos
Isoquinolinas/farmacologia , Tauopatias/fisiopatologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Amiloide/química , Aspergillus nidulans/metabolismo , Fungos/metabolismo , Humanos , Isoquinolinas/metabolismo , Microtúbulos/metabolismo , Neurônios/metabolismo , Príons/metabolismo , Agregados Proteicos/fisiologia , Agregação Patológica de Proteínas/metabolismo , Relação Estrutura-Atividade , Tauopatias/metabolismo , Proteínas tau/fisiologiaRESUMO
Accumulation and spread of tau in Alzheimer's disease and other tauopathies occur in a prion-like manner. However, the mechanisms and downstream consequences of tau trafficking remain largely unknown. We hypothesized that tau traffics from neurons to microglia via extracellular vesicles (EVs), leading to IL-6 generation and cognitive impairment. We assessed mice and neurons treated with anesthetics sevoflurane and desflurane, and applied nanobeam-sensor technology, an ultrasensitive method, to measure tau/p-tau amounts. Sevoflurane, but not desflurane, increased tau or p-tau amounts in blood, neuron culture medium, or EVs. Sevoflurane increased p-tau amounts in brain interstitial fluid. Microglia from tau knockout mice took up tau and p-tau when treated with sevoflurane-conditioned neuron culture medium, leading to IL-6 generation. Tau phosphorylation inhibitor lithium and EVs generation inhibitor GW4869 attenuated tau trafficking. GW4869 mitigated sevoflurane-induced cognitive impairment in mice. Thus, tau trafficking could occur from neurons to microglia to generate IL-6, leading to cognitive impairment.
Assuntos
Transporte Proteico/efeitos dos fármacos , Sevoflurano/farmacologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Anestésicos Inalatórios/farmacologia , Animais , Encéfalo/metabolismo , Disfunção Cognitiva/induzido quimicamente , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/fisiologia , Feminino , Hipocampo/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação , Transporte Proteico/fisiologia , Sevoflurano/metabolismo , Tauopatias/metabolismo , Tauopatias/fisiopatologia , Proteínas tau/fisiologiaRESUMO
Insoluble, fibrillar intraneuronal accumulation of the tau protein termed neurofibrillary tangles (NFTs), are characteristic hallmarks of Alzheimer's disease (AD). They play a significant role in the behavioral phenotypes of AD. Certain mice (rTg4510) constitutively express mutant human tau until transgene expression is inactivated by the administration of doxycycline (DOX). The present study aimed to determine the timing of the onset of memory impairment in rTg4510 mice and define the relationship between the extent of memory deficit and the duration of NFT overexpression. In 6-month-old (young) rTg4510 mice, both spatial memory and object recognition memory were impaired. These impairments were prevented by pre-treatment with DOX for 2 months. In parallel, the expression of NFTs decreased in the DOX-treated group. Ten-month-old (aged) rTg4510 mice showed severe impairments in memory performance. Pretreatment with DOX did not prevent these impairments. Increasing levels of NFTs were observed in aged rTg4510 mice. DOX treatment did not prevent tau pathology in aged rTg4510 mice. Expression of the autophagy markers LC3A and LC3B increased in rTg4510 mice, along with an increase in NFT formation. These results suggest that the clearance mechanisms of NFTs are impaired at 10 months of age.
Assuntos
Memória/fisiologia , Emaranhados Neurofibrilares/fisiologia , Tauopatias/fisiopatologia , Fatores Etários , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Tauopatias/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.