Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.397
Filtrar
1.
Nat Commun ; 12(1): 4863, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381050

RESUMO

Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer's disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.


Assuntos
Clusterina/metabolismo , Agregação Patológica de Proteínas/metabolismo , Proteínas tau/metabolismo , Animais , Clusterina/genética , Progressão da Doença , Endocitose , Humanos , Camundongos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Neurônios/patologia , Agregação Patológica de Proteínas/patologia , Ligação Proteica , alfa-Sinucleína/metabolismo , Proteínas tau/genética
2.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360787

RESUMO

The principal pathogenic event in Parkinson's disease is characterized by the conformational change of α-synuclein, which form pathological aggregates of misfolded proteins, and then accumulate in intraneuronal inclusions causing dopaminergic neuronal loss in specific brain regions. Over the last few years, a revolutionary theory has correlated Parkinson's disease and other neurological disorders with a shared mechanism, which determines α-synuclein aggregates and progresses in the host in a prion-like manner. In this review, the main characteristics shared between α-synuclein and prion protein are compared and the cofactors that influence the remodeling of native protein structures and pathogenetic mechanisms underlying neurodegeneration are discussed.


Assuntos
Doença de Parkinson , Doenças Priônicas , Agregados Proteicos , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia
4.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371878

RESUMO

Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3ß (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPß, and the concentration of Aß40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-ß expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.


Assuntos
Doença de Alzheimer/prevenção & controle , Encéfalo/efeitos dos fármacos , Suplementos Nutricionais , Plasma , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ração Animal , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Quinase 5 Dependente de Ciclina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fragmentos de Peptídeos/metabolismo , Fosforilação , Transdução de Sinais , Secagem por Atomização , Sus scrofa , Proteínas tau/metabolismo
5.
Lancet Neurol ; 20(9): 739-752, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34418401

RESUMO

BACKGROUND: Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes. METHODS: In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test. FINDINGS: Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau217, AUC=0·97 [0·94-0·99] for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92-1·00] for p-tau217, AUC=0·91 [0·82-1·00] for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91-0·96] for p-tau217, AUC=0·91 [0·88-0·94] for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88-0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86-0·93]; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230). INTERPRETATION: Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology. FUNDING: US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.


Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Degeneração Lobar Frontotemporal/diagnóstico , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Diagnóstico Diferencial , Feminino , Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação/fisiologia , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Estudos Retrospectivos , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano
6.
Alzheimers Res Ther ; 13(1): 138, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389066

RESUMO

BACKGROUND: Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer's disease (AD) and have been associated with amyloid-ß (Aß) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum. METHODS: We included 533 individuals (178 Aß-negative cognitively unimpaired (CU) subjects, 105 Aß-positive CU subjects, 122 Aß-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions. RESULTS: Across the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (all p < 0.001), indicative of a less optimal network organisation. Already in CU Aß-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology. CONCLUSIONS: Our data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo
7.
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
8.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445147

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly. Progressive accumulation of insoluble isoforms of amyloid-ß peptide (Aß) and tau protein are the major neuropathologic hallmarks, and the loss of cholinergic pathways underlies cognitive deficits in patients. Recently, glial involvement has gained interest regarding its effect on preservation and impairment of brain integrity. The limbic system, including temporal lobe regions and the olfactory bulb, is particularly affected in the early stages. In the early 1980s, the reduced expression of the somatostatin neuropeptide was described in AD. However, over the last three decades, research on somatostatin in Alzheimer's disease has been scarce in humans. Therefore, the aim of this study was to stereologically quantify the expression of somatostatin in the human hippocampus and olfactory bulb and analyze its spatial distribution with respect to that of Aß and au neuropathologic proteins and astroglia. The results indicate that somatostatin-expressing cells are reduced by 50% in the hippocampus but are preserved in the olfactory bulb. Interestingly, the coexpression of somatostatin with the Aß peptide is very common but not with the tau protein. Finally, the coexpression of somatostatin with astrocytes is rare, although their spatial distribution is very similar. Altogether, we can conclude that somatostatin expression is highly reduced in the human hippocampus, but not the olfactory bulb, and may play a role in Alzheimer's disease pathogenesis.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Sistema Límbico/metabolismo , Sistema Límbico/patologia , Somatostatina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bulbo Olfatório/metabolismo , Bulbo Olfatório/patologia , Proteínas tau/metabolismo
9.
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
10.
ACS Chem Neurosci ; 12(18): 3487-3496, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34464084

RESUMO

Alzheimer's disease and primary tauopathies are characterized by the presence of tau pathology in brain. Several tau positron emission tomography (PET) tracers have been developed and studied in Alzheimer's disease (AD), but there is still a lack of 4R-tau specific tracers for non-AD tauopathies. We here present the first computational study on the binding profiles of four tau different PET tracers, PI2620, CBD2115, PM-PBB3, and MK6240, to corticobasal degeneration (CBD) tau. The in silico results showed different preferences for the various binding sites on the 4R fibril, and especially an entry site, a concave site, and a core site showed high binding affinity to these tracers. The core site and entry site both showed higher binding affinity than the surface sites, but the tracers were less likely to enter these sites. PI2620, CBD2115, and PM-PBB3 all showed higher binding affinities to CBD tau than the 3R/4R tracer MK6240. The same strategy has also been applied to AD tau fibrils, and significant differences in selectivity of binding sites were also observed. A higher binding affinity was observed for CBD2115 and PM-PBB3 to AD tau compared to PI2620. None of the studied tracers showed a selectivity for 4R compared to 3R/4R tau. This study clearly shows that identified binding sites from cryo-EM with low resolution can be further refined by metadynamics simulations in order to provide atomic resolution of the binding modes as well as of the thermodynamic properties.


Assuntos
Doença de Alzheimer , Tauopatias , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/metabolismo , Humanos , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo
11.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204308

RESUMO

Globally, Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disorders associated with cognitive decline and memory deficits due to beta-amyloid deposition (Aß) and tau protein hyperphosphorylation. To date, approximately 47 million people worldwide have AD. This figure will rise to an estimated 75.6 million by 2030 and 135.5 million by 2050. According to the literature, the efficacy of conventional medications for AD is statistically substantial, but clinical relevance is restricted to disease slowing rather than reversal. Withaferin A (WA) is a steroidal lactone glycowithanolides, a secondary metabolite with comprehensive biological effects. Biosynthetically, it is derived from Withania somnifera (Ashwagandha) and Acnistus breviflorus (Gallinero) through the mevalonate and non-mevalonate pathways. Mounting evidence shows that WA possesses inhibitory activities against developing a pathological marker of Alzheimer's diseases. Several cellular and animal models' particulates to AD have been conducted to assess the underlying protective effect of WA. In AD, the neuroprotective potential of WA is mediated by reduction of beta-amyloid plaque aggregation, tau protein accumulation, regulation of heat shock proteins, and inhibition of oxidative and inflammatory constituents. Despite the various preclinical studies on WA's therapeutic potentiality, less is known regarding its definite efficacy in humans for AD. Accordingly, the present study focuses on the biosynthesis of WA, the epidemiology and pathophysiology of AD, and finally the therapeutic potential of WA for the treatment and prevention of AD, highlighting the research and augmentation of new therapeutic approaches. Further clinical trials are necessary for evaluating the safety profile and confirming WA's neuroprotective potency against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Vitanolídeos/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Humanos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Placa Amiloide/tratamento farmacológico , Solanaceae/metabolismo , Withania/metabolismo , Vitanolídeos/metabolismo , Proteínas tau/metabolismo
12.
Biochemistry (Mosc) ; 86(6): 737-745, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225596

RESUMO

The review summarizes the results of studies on the cellular and molecular mechanisms mediating the impact of stress on the pathogenesis of neurodegenerative brain pathologies (Alzheimer's disease, Parkinson's disease, etc.) and presents current information on the role of stress in the hyperphosphorylation of tau protein, aggregation of beta-amyloid, and hyperactivation of the hypothalamic-pituitary-adrenal axis involved in the hyperproduction of factors that contribute to the pathogenetic role of stress in neurodegeneration. The data on the participation of microglia in the effects of stress on the pathogenesis of neurodegenerative diseases are presented.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Psicológico , Proteínas tau/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Demência/etiologia , Demência/metabolismo , Demência/fisiopatologia , Humanos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Fosforilação , Agregação Patológica de Proteínas , Processamento de Proteína Pós-Traducional
13.
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
14.
Nat Commun ; 12(1): 4304, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262030

RESUMO

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73-0.87] and 0.92 [95% CI 0.89-0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS.


Assuntos
Doença de Alzheimer/diagnóstico , Síndrome de Down/diagnóstico , Proteínas tau/sangue , Adulto , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Área Sob a Curva , Atrofia , Biomarcadores/sangue , Biomarcadores/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Cognição , Estudos Transversais , Progressão da Doença , Síndrome de Down/sangue , Síndrome de Down/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Fosforilação , Proteínas tau/metabolismo
15.
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
16.
Med Sci Monit ; 27: e934077, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34305135

RESUMO

Current treatments for patients with Alzheimer's disease aim to improve behavioral, cognitive, and non-cognitive symptoms. There have been no new drug approvals for preventing or treating Alzheimer's disease for more than two decades. Drug development in Alzheimer's disease aims to identify disease-modifying therapies that will delay or slow the clinical course of this disease. More than 50% of the current Alzheimer's disease drug pipeline now involves immunotherapies or oral small molecule agents. The most promising disease-modifying drug targets are amyloid ß and tau protein. In June 2021, aducanumab, a humanized recombinant monoclonal antibody to amyloid ß, was the first potential disease-modifying therapy approved by the US Food and Drug Administration (FDA) to treat Alzheimer's disease and mild cognitive impairment. Accelerated approval of aducanumab was based on the results of only one of two phase 3 clinical trials. Several clinical trials of targeted disease-modifying immunotherapies to the tau protein and amyloid ß that commenced before the current COVID-19 pandemic have been delayed. This Editorial aims to provide an update on past, present, and future disease-modifying therapies in Alzheimer's disease, including targeted therapies for amyloid ß and tau protein.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/imunologia , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Tauopatias/tratamento farmacológico
17.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299250

RESUMO

The 3xTg-AD mouse is a widely used model in the study of Alzheimer's Disease (AD). It has been extensively characterized from both the anatomical and behavioral point of view, but poorly studied at the transcriptomic level. For the first time, we characterize the whole blood transcriptome of the 3xTg-AD mouse at three and six months of age and evaluate how its gene expression is modulated by transcranial direct current stimulation (tDCS). RNA-seq analysis revealed 183 differentially expressed genes (DEGs) that represent a direct signature of the genetic background of the mouse. Moreover, in the 6-month-old 3xTg-AD mice, we observed a high number of DEGs that could represent good peripheral biomarkers of AD symptomatology onset. Finally, tDCS was associated with gene expression changes in the 3xTg-AD, but not in the control mice. In conclusion, this study provides an in-depth molecular characterization of the 3xTg-AD mouse and suggests that blood gene expression can be used to identify new biomarkers of AD progression and treatment effects.


Assuntos
Doença de Alzheimer/genética , Estimulação Transcraniana por Corrente Contínua/efeitos adversos , Transcriptoma/genética , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Sequenciamento Completo do Exoma/métodos , Proteínas tau/metabolismo
18.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298984

RESUMO

While much of biomedical research since the middle of the twentieth century has focused on molecular pathways inside the cell, there is increasing evidence that extracellular signaling pathways are also critically important in health and disease. The neuromodulators norepinephrine (NE), serotonin (5-hydroxytryptamine, 5HT), dopamine (DA), acetylcholine (ACH), and melatonin (MT) are extracellular signaling molecules that are distributed throughout the brain and modulate many disease processes. The effects of these five neuromodulators on Alzheimer's disease (AD) are briefly examined in this paper, and it is hypothesized that each of the five molecules has a u-shaped (or Janus-faced) dose-response curve, wherein too little or too much signaling is pathological in AD and possibly other diseases. In particular it is suggested that NE is largely functionally opposed to 5HT, ACH, MT, and possibly DA in AD. In this scenario, physiological "balance" between the noradrenergic tone and that of the other three or four modulators is most healthy. If NE is largely functionally opposed to other prominent neuromodulators in AD, this may suggest novel combinations of pharmacological agents to counteract this disease. It is also suggested that the majority of cases of AD and possibly other diseases involve an excess of noradrenergic tone and a collective deficit of the other four modulators.


Assuntos
Doença de Alzheimer/fisiopatologia , Neurotransmissores/antagonistas & inibidores , Norepinefrina/fisiologia , Transmissão Sináptica/fisiologia , Adrenérgicos/administração & dosagem , Adrenérgicos/uso terapêutico , Neurônios Adrenérgicos/fisiologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Química Encefálica , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Melatonina/uso terapêutico , Camundongos , Modelos Neurológicos , Neurotransmissores/fisiologia , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Norepinefrina/farmacologia , Fosforilação , Processamento de Proteína Pós-Traducional , Ratos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/fisiologia , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Proteínas tau/metabolismo
19.
Nat Commun ; 12(1): 4634, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330900

RESUMO

Amyloid-ß peptide (Aß) forms metastable oligomers >50 kDa, termed AßOs, that are more effective than Aß amyloid fibrils at triggering Alzheimer's disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aß accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AßO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AßO formation and the high endo-lysosomal Aß concentration together enable extensive AßO formation of Aß42 under physiological conditions. Exploiting the enhanced AßO formation of the dimeric Aß variant dimAß we furthermore demonstrate targeting of AßOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AßOs.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Endossomos/metabolismo , Lisossomos/metabolismo , Neurônios/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/química , Animais , Linhagem Celular Tumoral , Células Cultivadas , Espinhas Dendríticas/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Neurônios/citologia , Multimerização Proteica
20.
Sci Total Environ ; 794: 148732, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34323745

RESUMO

It has been reported that microcystin-leucine-arginine (MC-LR) can enter into the brain and demonstrate neurotoxicity resulting in learning and memory deficits. While, there is still a lack of clear understanding of the related molecular mechanisms. In this study, we observed ß-amyloid (Aß) accumulation and tau hyperphosphorylation (p-tau) at sites of Ser396 and Thr205 in mouse hippocampus and cortex, Alzheimer's disease (AD) like changes, after chronic exposure to MC-LR at different concentrations (1, 7.5, 15 and 30 µg/L) for 180 days. The hallmarks of AD are characterized by senile plaques and neurofibrillary tangles (NFT), with associated loss of neurons, resulting in cognitive impairment and dementia. Similarly, the production of Aß and tau hyperphosphorylation was also detected in HT-22 cells treated with MC-LR. In addition, MC-LR promoted increased expressions of BACE1 and PS1, but reduced mRNA expressions of ADAM family members both in vivo and in vitro, promoting the Aß production. Moreover, we identified Akt/GSK-3ß signal pathway mediated the Aß and p-tau accumulation, bringing about Alzheimer's disease-like changes. Furthermore, microglial cells were activated in those mice exposed to MC-LR. Inflammatory cytokines were also found being activated to release in vitro. In conclusion, this study could provide a clue for MC-LR-induced neurotoxicity, which gave insights into the environmental risks of Alzheimer's disease.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Proteínas tau , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Quinase 3 da Glicogênio Sintase , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Proteínas tau/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...