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1.
Nat Commun ; 12(1): 5338, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504072

RESUMO

Molecular chaperones, including Hsp70/J-domain protein (JDP) families, play central roles in binding substrates to prevent their aggregation. How JDPs select different conformations of substrates remains poorly understood. Here, we report an interaction between the JDP DnaJC7 and tau that efficiently suppresses tau aggregation in vitro and in cells. DnaJC7 binds preferentially to natively folded wild-type tau, but disease-associated mutants in tau reduce chaperone binding affinity. We identify that DnaJC7 uses a single TPR domain to recognize a ß-turn structural element in tau that contains the 275VQIINK280 amyloid motif. Wild-type tau, but not mutant, ß-turn structural elements can block full-length tau binding to DnaJC7. These data suggest DnaJC7 preferentially binds and stabilizes natively folded conformations of tau to prevent tau conversion into amyloids. Our work identifies a novel mechanism of tau aggregation regulation that can be exploited as both a diagnostic and a therapeutic intervention.


Assuntos
Amiloide/química , Proteínas de Choque Térmico/química , Chaperonas Moleculares/química , Agregados Proteicos/genética , Tauopatias/genética , Proteínas tau/química , Amiloide/antagonistas & inibidores , Amiloide/genética , Amiloide/metabolismo , Animais , Sítios de Ligação , Encéfalo/metabolismo , Encéfalo/patologia , Clonagem Molecular , Modelos Animais de Doenças , Expressão Gênica , Células HEK293 , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Camundongos , Modelos Moleculares , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutação , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Tauopatias/metabolismo , Tauopatias/patologia , Termodinâmica , Proteínas tau/genética , Proteínas tau/metabolismo
2.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576308

RESUMO

Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.


Assuntos
Núcleo Celular/metabolismo , Sinapses/metabolismo , Tauopatias/metabolismo , Proteínas tau/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Humanos , Sinapses/fisiologia , Proteínas tau/química
3.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575885

RESUMO

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/metabolismo
4.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502116

RESUMO

Tau protein plays a critical role in the assembly, stabilization, and modulation of microtubules, which are important for the normal function of neurons and the brain. In diseased conditions, several pathological modifications of tau protein manifest. These changes lead to tau protein aggregation and the formation of paired helical filaments (PHF) and neurofibrillary tangles (NFT), which are common hallmarks of Alzheimer's disease and other tauopathies. The accumulation of PHFs and NFTs results in impairment of physiological functions, apoptosis, and neuronal loss, which is reflected as cognitive impairment, and in the late stages of the disease, leads to death. The causes of this pathological transformation of tau protein haven't been fully understood yet. In both physiological and pathological conditions, tau interacts with several proteins which maintain their proper function or can participate in their pathological modifications. Interaction partners of tau protein and associated molecular pathways can either initiate and drive the tau pathology or can act neuroprotective, by reducing pathological tau proteins or inflammation. In this review, we focus on the tau as a multifunctional protein and its known interacting partners active in regulations of different processes and the roles of these proteins in Alzheimer's disease and tauopathies.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Proteínas de Transporte/metabolismo , Tauopatias/etiologia , Tauopatias/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Animais , Biomarcadores , Suscetibilidade a Doenças , Humanos , Neurônios/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional , Proteólise , Transdução de Sinais , Tauopatias/patologia
5.
FASEB J ; 35(9): e21807, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34384141

RESUMO

Pneumonia causes short- and long-term cognitive dysfunction in a high proportion of patients, although the mechanism(s) responsible for this effect are unknown. Here, we tested the hypothesis that pneumonia-elicited cytotoxic amyloid and tau variants: (1) are present in the circulation during infection; (2) lead to impairment of long-term potentiation; and, (3) inhibit long-term potentiation dependent upon tau. Cytotoxic amyloid and tau species were recovered from the blood and the hippocampus following pneumonia, and they were present in the extracorporeal membrane oxygenation oxygenators of patients with pneumonia, especially in those who died. Introduction of immunopurified blood-borne amyloid and tau into either the airways or the blood of uninfected animals acutely and chronically impaired hippocampal information processing. In contrast, the infection did not impair long-term potentiation in tau knockout mice and the amyloid- and tau-dependent disruption in hippocampal signaling was less severe in tau knockout mice. Moreover, the infection did not elicit cytotoxic amyloid and tau variants in tau knockout mice. Therefore, pneumonia initiates a tauopathy that contributes to cognitive dysfunction.


Assuntos
Pneumonia/complicações , Tauopatias/etiologia , Adulto , Idoso , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Humanos , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Pneumonia/metabolismo , Ratos , Tauopatias/metabolismo , Adulto Jovem , Proteínas tau/metabolismo
6.
DNA Cell Biol ; 40(9): 1185-1199, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34379990

RESUMO

Clinical progression of tauopathies may result from transcellular propagation of pathogenic Tau seeds with the possible involvement of extracellular vesicles (EVs) as transport vectors. We established a cell model for investigating EV delivery of proteins, since the mechanism regulating EV cargo delivery to recipient cells is poorly understood. In our cell model, EVs are readily internalized and accumulate in degradative organelles (DOs). We then show for the first time that in this acidic compartment, profibrillogenic Tau delivered by EVs interacts with Tau expressed by the recipient cells and cause its accumulation by a process that involves the participation of autophagy. Thus, the degradative compartment of cells may represent the subcellular site initiating a cascade of events resulting in early hallmarks of tauopathies. These are characterized by seeded Tau accumulation, pathology-associated epitopes, DO stress, and cytotoxicity. The involvement of autophagy to this process and the relative accessibility of the degradative pathway for extracellular agents, support possible modes of intervention to slow down the progression of neurodegeneration.


Assuntos
Vesículas Extracelulares/metabolismo , Organelas/metabolismo , Tauopatias , Proteínas tau/fisiologia , Animais , Linhagem Celular , Camundongos , Células-Tronco Multipotentes , Tauopatias/metabolismo , Tauopatias/patologia
7.
Molecules ; 26(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34443629

RESUMO

Tau is a highly soluble protein mainly localized at a cytoplasmic level in the neuronal cells, which plays a crucial role in the regulation of microtubule dynamic stability. Recent studies have demonstrated that several factors, such as hyperphosphorylation or alterations of Tau metabolism, may contribute to the pathological accumulation of protein aggregates, which can result in neuronal death and the onset of a number of neurological disorders called Tauopathies. At present, there are no available therapeutic remedies able to reduce Tau aggregation, nor are there any structural clues or guidelines for the rational identification of compounds preventing the accumulation of protein aggregates. To help identify the structural properties required for anti-Tau aggregation activity, we performed extensive chemoinformatics analyses on a dataset of Tau ligands reported in ChEMBL. The performed analyses allowed us to identify a set of molecular properties that are in common between known active ligands. Moreover, extensive analyses of the fragment composition of reported ligands led to the identification of chemical moieties and fragment combinations prevalent in the more active compounds. Interestingly, many of these fragments were arranged in recurring frameworks, some of which were clearly present in compounds currently under clinical investigation. This work represents the first in-depth chemoinformatics study of the molecular properties, constituting fragments and similarity profiles, of known Tau aggregation inhibitors. The datasets of compounds employed for the analyses, the identified molecular fragments and their combinations are made publicly available as supplementary material.


Assuntos
Preparações Farmacêuticas/administração & dosagem , Tauopatias/tratamento farmacológico , Proteínas tau/metabolismo , Quimioinformática/métodos , Humanos , Ligantes , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Agregados Proteicos/efeitos dos fármacos , Tauopatias/metabolismo
8.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360858

RESUMO

Tauopathies are neurodegenerative diseases characterized by abnormal metabolism of misfolded tau proteins and are progressive. Pathological phosphorylation of tau occurs in the retinal ganglion cells (RGCs) after optic nerve injuries. Cyclin-dependent kinase-5 (Cdk5) causes hyperphosphorylation of tau. To determine the roles played by Cdk5 in retinal degeneration, roscovitine, a Cdk5 inhibitor, was injected intravitreally after optic nerve crush (ONC). The neuroprotective effect of roscovitine was determined by the number of Tuj-1-stained RGCs on day 7. The change in the levels of phosphorylated tau, calpain-1, and cleaved α-fodrin was determined by immunoblots on day 3. The expression of P35/P25, a Cdk5 activator, in the RGCs was determined by immunohistochemistry. The results showed that roscovitine reduced the level of phosphorylated tau by 3.5- to 1.6-fold. Calpain-1 (2.1-fold) and cleaved α-fodrin (1.5-fold) were increased on day 3, suggesting that the calpain signaling pathway was activated. P35/P25 was accumulated in the RGCs that were poorly stained by Tuj-1. Calpain inhibition also reduced the increase in phosphorylated tau. The number of RGCs decreased from 2191 ± 178 (sham) to 1216 ± 122 cells/mm2 on day 7, and roscovitine preserved the level at 1622 ± 130 cells/mm2. We conclude that the calpain-mediated activation of Cdk5 is associated with the pathologic phosphorylation of tau.


Assuntos
Quinase 5 Dependente de Ciclina/fisiologia , Traumatismos do Nervo Óptico , Células Ganglionares da Retina , Tauopatias , Proteínas tau/metabolismo , Animais , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Traumatismos do Nervo Óptico/metabolismo , Traumatismos do Nervo Óptico/patologia , Fosforilação , Ratos , Ratos Wistar , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Roscovitina/farmacologia , Tauopatias/metabolismo , Tauopatias/patologia
9.
J Neurochem ; 158(6): 1394-1411, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34272732

RESUMO

The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD-TAU) and the TDP-43 proteinopathy of FTLD-TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD-TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD-TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention.


Assuntos
Prosencéfalo Basal/metabolismo , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/metabolismo , Demência/metabolismo , Degeneração Neural/metabolismo , Receptores Colinérgicos/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Animais , Prosencéfalo Basal/patologia , Neurônios Colinérgicos/patologia , Demência/patologia , Demência/psicologia , Suscetibilidade a Doenças/metabolismo , Suscetibilidade a Doenças/patologia , Suscetibilidade a Doenças/psicologia , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Degeneração Lobar Frontotemporal/psicologia , Humanos , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/psicologia , Degeneração Neural/patologia , Degeneração Neural/psicologia , Resiliência Psicológica , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/psicologia
10.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299093

RESUMO

Neurofibrillary tangles, which consist of highly phosphorylated tau protein, and senile plaques (SPs) are pathological hallmarks of Alzheimer's disease (AD). In swollen axons, many autophagic vacuoles are observed around SP in the AD brain. This suggests that autophagy function is disturbed in AD. We used a neuronal cellular model of tauopathy (M1C cells), which harbors wild type tau (4R0N), to assess the effects of the lysosomotrophic agent NH4Cl, and autophagy inhibitors chloroquine and 3 methyladenine (3MA). It was found that chloroquine, NH4Cl and 3MA markedly increased tau accumulation. Thus, autophagy lysosomal system disturbances disturbed the degradation mechanisms of tau protein. Other studies also revealed that tau protein, including aggregated tau, is degraded via the autophagy lysosome system. Phosphorylated and C terminal truncated tau were also reported to disturb autophagy function. As a therapeutic strategy, autophagy upregulation was suggested. Thus far, as autophagy modulators, rapamycin, mTOCR1 inhibitor and its analogues, lithium, metformin, clonidine, curcumin, nicotinamide, bexaroten, and torehalose have been proposed. As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics.


Assuntos
Doença de Alzheimer/patologia , Autofagia , Tauopatias/patologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Animais , Humanos , Tauopatias/metabolismo
11.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200180

RESUMO

Tauopathies are a heterogeneous class of neurodegenerative diseases characterized by intracellular inclusions of aggregated tau proteins. Tau aggregates in different tauopathies have distinct structural features and can be found in different cell types. Transgenic animal models overexpressing human tau have been used for over two decades in the research of tau pathology. However, these models poorly recapitulate the heterogeneity of tauopathies found in human brains. Recent findings demonstrate that injection of purified tau aggregates from the brains of human tauopathy patients recapitulates both the structural features and cell-type specificity of the tau pathology of the donor tauopathy. These models may therefore have unique translational value in the study of functional consequences of tau pathology, tau-based diagnostics, and tau targeting therapeutics. This review provides an update of the literature relating to seeding-based tauopathy and their potential applications.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Modelos Animais de Doenças , Agregados Proteicos , Tauopatias/patologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Camundongos , Tauopatias/metabolismo , Proteínas tau/química
12.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205516

RESUMO

Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncovalent and covalent interactions. Thus, Michael's addition appears as a feasible type of interaction involving an α, ß unsaturated carbonyl moiety to avoid pathological confirmation and further cytotoxicity. Moreover, we isolated three compounds from Antarctic lichens Cladonia cariosa and Himantormia lugubris: protolichesterinic acid (1), fumarprotocetraric acid (2), and lichesterinic acid (3). The maleimide cysteine labeling assay showed that compounds 1, 2, and 3 inhibit at 50 µM, but compounds 2 and 3 are statistically significant. Based on its inhibition capacity, we decided to test compound 2 further. Thus, our results suggest that compound 2 remodel soluble oligomers and diminish ß sheet content, as demonstrated through ThT experiments. Hence, we added externally treated oligomers with compound 2 to demonstrate that they are harmless in cell culture. First, the morphology of cells in the presence of aggregates does not suffer evident changes compared to the control. Additionally, the externally added aggregates do not provoke a substantial LDH release compared to the control, indicating that treated oligomers do not provoke membrane damage in cell culture compared with aggregates alone. Thus, in the present work, we demonstrated that Michael's acceptors found in lichens could serve as a scaffold to explore different mechanisms of action to turn tau aggregates into harmless species.


Assuntos
Fumaratos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Regiões Antárticas , Ascomicetos/metabolismo , Linhagem Celular Tumoral , Humanos , Líquens/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Parmeliaceae/metabolismo , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo
13.
PLoS Comput Biol ; 17(7): e1009258, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34314441

RESUMO

Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer's disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology. We simulated the spatiotemporal profiles of soluble and insoluble tau species in a multicompartment, two-neuron system using biologically plausible parameters and time scales. Changes in the balance of tau transport feedback parameters can elicit anterograde and retrograde biases in the distributions of soluble and insoluble tau between compartments in the system. Aggregation and fragmentation parameters can also perturb this balance, suggesting a complex interplay between these distinct molecular processes. Critically, we show that the model faithfully recreates the characteristic network spread biases in both AD-like and non-AD-like mouse tauopathy models. Tau transport feedback may therefore help link microscopic differences in tau conformational states and the resulting variety in clinical presentations.


Assuntos
Transporte Axonal/fisiologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Animais , Biologia Computacional , Simulação por Computador , Dendritos/metabolismo , Modelos Animais de Doenças , Retroalimentação Fisiológica , Humanos , Camundongos , Modelos Neurológicos , Doenças Neurodegenerativas/metabolismo , Conformação Proteica , Dobramento de Proteína , Solubilidade , Análise Espaço-Temporal , Tauopatias/metabolismo , Proteínas tau/química
14.
Neuron ; 109(15): 2413-2426.e7, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34157306

RESUMO

APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here, we show that overexpressing an apoE metabolic receptor, LDLR (low-density lipoprotein receptor), in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression and is associated with suppressed microglial activation as in apoE-deficient microglia. ApoE deficiency and LDLR OX strongly drive microglial immunometabolism toward enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs) and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy.


Assuntos
Apolipoproteínas E/metabolismo , Degeneração Neural/metabolismo , Receptores de LDL/metabolismo , Tauopatias/metabolismo , Animais , Apolipoproteínas E/genética , Masculino , Camundongos , Camundongos Knockout , Microglia/metabolismo , Tauopatias/genética
15.
Sci Rep ; 11(1): 9623, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953293

RESUMO

Tau, a family of microtubule-associated proteins, forms abnormal intracellular inclusions, so-called tau pathology, in a range of neurodegenerative diseases collectively known as tauopathies. The rTg4510 mouse model is a well-characterized bitransgenic F1 hybrid mouse model of tauopathy, which was obtained by crossing a Camk2α-tTA mouse line (on a C57BL/6 J background) with a tetO-MAPT*P301L mouse line (on a FVB/NJ background). The aim of this study was to investigate the effects of the genetic background and sex on the accumulation of tau pathology in reciprocal F1 hybrids of rTg4510 mice, i.e., rTg4510 on the (C57BL/6 J × FVB/NJ)F1 background (rTg4510_CxF) and on the (FVB/NJ × C57BL/6 J)F1 background (rTg4510_FxC). As compared with rTg4510_CxF mice, the rTg4510_FxC mice showed marked levels of tau pathology in the forebrain. Biochemical analyses indicated that the accumulation of abnormal tau species was accelerated in rTg4510_FxC mice. There were strong effects of the genetic background on the differential accumulation of tau pathology in rTg4510 mice, while sex had no apparent effect. Interestingly, midline-1 (Mid1) was identified as a candidate gene associated with this difference and exhibited significant up/downregulation according to the genetic background. Mid1 silencing with siRNA induced pathological phosphorylation of tau in HEK293T cells that stably expressed human tau with the P301L mutation, suggesting the role of Mid1 in pathological alterations of tau. Elucidation of the underlying mechanisms will provide novel insights into the accumulation of tau pathology and is expected to be especially informative to researchers for the continued development of therapeutic interventions for tauopathies.


Assuntos
Encéfalo/metabolismo , Corpos de Inclusão/metabolismo , Neurônios/metabolismo , Tauopatias/metabolismo , Proteínas tau/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Corpos de Inclusão/patologia , Camundongos , Camundongos Transgênicos , Neurônios/patologia , Fosforilação , Tauopatias/genética , Tauopatias/patologia , Proteínas tau/genética
16.
Exp Neurol ; 343: 113756, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33989658

RESUMO

Alzheimer's disease (AD) is characterised by the accumulation of intracytoplasmic aggregates of tau protein, which are suggested to spread in a prion-like manner between interconnected brain regions. This spreading is mediated by the secretion and uptake of tau from the extracellular space or direct cell-to-cell transmission through cellular protrusions. The prion-like tau then converts the endogenous, normal tau into pathological forms, resulting in neurodegeneration. The endoplasmic reticulum/Golgi-independent tau secretion through unconventional secretory pathways involves delivering misfolded and aggregated tau to the plasma membrane and its release into the extracellular space by non-vesicular and vesicular mechanisms. Although cytoplasmic tau was thought to be released only from degenerating cells, studies now show that cells constitutively secrete tau at low levels under physiological conditions. The mechanisms of secretion of tau under physiological and pathological conditions remain unclear. Therefore, a better understanding of these pathways is essential for developing therapeutic approaches that can target prion-like tau forms to prevent neurodegeneration progression in AD. This review focuses on unconventional secretion pathways involved in the spread of tau pathology in AD and presents these pathways as prospective areas for future AD drug discovery and development.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Agregação Patológica de Proteínas/metabolismo , Tauopatias/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Comunicação Celular/fisiologia , Humanos , Agregação Patológica de Proteínas/patologia , Tauopatias/patologia
17.
Biochim Biophys Acta Mol Basis Dis ; 1867(8): 166162, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33940164

RESUMO

Tau is a microtubule-stabilizing protein that plays an important role in the formation of axonal microtubules in neurons. Phosphorylated tau (p-Tau) has received great attention in the field of Alzheimer's disease (AD) as a potential therapeutic target due to its involvement with synaptic damage and neuronal dysfunction. Mounting evidence suggests that amyloid beta (Aß)-targeted clinical trials continuously failed; therefore, it is important to consider alternative therapeutic strategies such as p-tau-PROTACs targeted small molecules for AD and other tauopathies. The present article describes the characteristics of tau biology, structure, and function in both healthy and pathological states in AD. It also explains data from studies that have identified the involvement of p-tau in neuronal damage and synaptic and cognitive functions in AD. Current article also covers several aspects, including small molecule inhibitors, and the development of p-tau-PROTACs targeted drug molecules to treat patients with AD and other tauopathies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Fosforilação/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
18.
Biochemistry ; 60(21): 1658-1669, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34009955

RESUMO

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/fisiologia
19.
J Neurosci ; 41(24): 5138-5156, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-33972400

RESUMO

Protein aggregation can induce explicit neurotoxic events that trigger a number of presently untreatable neurodegenerative disorders. Chaperones, on the other hand, play a neuroprotective role because of their ability to unfold and refold abnormal proteins. The progressive nature of neurotoxic events makes it important to discover endogenous factors that affect pathologic and molecular phenotypes of neurodegeneration in animal models. Here, we identified microtubule-associated protein tau, and chaperones Hsp70 (heat shock protein 70) and DNAJA1 (DJ2) as endogenous substrates of cereblon (CRBN), a substrate-recruiting subunit of cullin4-RING-E3-ligase. This recruitment results in ubiquitin-mediated degradation of tau, Hsp70, and DJ2. Knocking out CRBN enhances the chaperone activity of DJ2, resulting in decreased phosphorylation and aggregation of tau, improved association of tau with microtubules, and reduced accumulation of pathologic tau across brain. Functionally abundant DJ2 could prevent tau aggregation induced by various factors like okadaic acid and heparin. Depletion of CRBN also decreases the activity of tau-kinases including GSK3α/ß, ERK, and p38. Intriguingly, we found a high expression of CRBN and low levels of DJ2 in neuronal tissues of 5XFAD and APP knock-in male mouse models of Alzheimer's disease. This implies that CRBN-mediated DJ2/Hsp70 pathway may be compromised in neurodegeneration. Being one of the primary pathogenic events, elevated CRBN can be a contributing factor for tauopathies. Our data provide a functional link between CRBN and DJ2/Hsp70 chaperone machinery in abolishing the cytotoxicity of aggregation-prone tau and suggest that Crbn -/- mice serve as an animal model of resistance against tauopathies for further exploration of the molecular mechanisms of neurodegeneration.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Tauopatias/patologia , Ubiquitina-Proteína Ligases/metabolismo , Proteínas tau/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Degeneração Neural , Tauopatias/metabolismo
20.
Nature ; 594(7861): 117-123, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34012113

RESUMO

The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes1,2. Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site3. MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies4. Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies5 and Parkinson's disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces-whereas silencing MAPT-AS1 expression increases-neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs6, with particular relevance for proteostasis in neurodegeneration.


Assuntos
Biossíntese de Proteínas/genética , Proteostase/genética , RNA Antissenso/genética , Tauopatias/genética , Tauopatias/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Idoso , Animais , Sítios de Ligação , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Diferenciação Celular , Progressão da Doença , Feminino , Humanos , Sítios Internos de Entrada Ribossomal/genética , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Ribossomos/metabolismo , Proteínas tau/biossíntese
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