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1.
Nat Commun ; 11(1): 4634, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929078

RESUMO

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.


Assuntos
Cromatina/metabolismo , Corpo Estriado/enzimologia , Dependência de Heroína/enzimologia , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Animais , Sequência de Bases , Comportamento Animal/efeitos dos fármacos , Sinais (Psicologia) , Genoma , Células HEK293 , Heroína/efeitos adversos , Humanos , Masculino , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , Ratos Long-Evans , Autoadministração , Transcrição Genética/efeitos dos fármacos , Proteínas tau/metabolismo
2.
Nat Commun ; 11(1): 4305, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855391

RESUMO

Oligomeric assemblies of tau and the RNA-binding proteins (RBPs) Musashi (MSI) are reported in Alzheimer's disease (AD). However, the role of MSI and tau interaction in their aggregation process and its effects are nor clearly known in neurodegenerative diseases. Here, we investigated the expression and cellular localization of MSI1 and MSI2 in the brains tissues of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as in the wild-type mice and tau knock-out and P301L tau mouse models. We observed that formation of pathologically relevant protein inclusions was driven by the aberrant interactions between MSI and tau in the nuclei associated with age-dependent extracellular depositions of tau/MSI complexes. Furthermore, tau and MSI interactions induced impairment of nuclear/cytoplasm transport, chromatin remodeling and nuclear lamina formation. Our findings provide mechanistic insight for pathological accumulation of MSI/tau aggregates providing a potential basis for therapeutic interventions in neurodegenerative proteinopathies.


Assuntos
Núcleo Celular/patologia , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/patologia , Proteínas de Ligação a RNA/metabolismo , Proteínas tau/metabolismo , Transporte Ativo do Núcleo Celular , Idoso , Idoso de 80 Anos ou mais , Animais , Núcleo Celular/metabolismo , Montagem e Desmontagem da Cromatina , Citoplasma/metabolismo , Modelos Animais de Doenças , Feminino , Lobo Frontal/citologia , Lobo Frontal/patologia , Células HEK293 , Humanos , Corpos de Inclusão/patologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Agregados Proteicos , Ligação Proteica , Proteínas tau/genética
3.
PLoS Biol ; 18(8): e3000851, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822389

RESUMO

High levels of the amyloid-beta (Aß) peptide have been shown to disrupt neuronal function and induce hyperexcitability, but it is unclear what effects Aß-associated hyperexcitability may have on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to model the impact of human APP (hAPP)/Aß accumulation on tauopathy in the entorhinal cortex-hippocampal (EC-HIPP) network, we demonstrate that hAPP overexpression aggravates EC-Tau aggregation and accelerates pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/Aß, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chronic chemogenetic attenuation of EC neuronal hyperactivity led to reduced hAPP/Aß accumulation and reduced pathological tau spread into downstream hippocampus. These data strongly support the hypothesis that in Alzheimer's disease (AD), Aß-associated hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD pathology in vivo.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Córtex Entorrinal/metabolismo , Tauopatias/genética , Proteínas tau/genética , Potenciais de Ação/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Eletrodos Implantados , Córtex Entorrinal/patologia , Feminino , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Agregados Proteicos , Técnicas Estereotáxicas , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/terapia , Ritmo Teta/fisiologia , Transdução Genética , Transgenes , Proteínas tau/metabolismo
4.
PLoS One ; 15(8): e0237153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32791516

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by cognitive dysfunction and memory loss as the main symptoms. The deposition of amyloid beta (Aß) and tau hyperphosphorylation are hallmarks of AD and are major therapeutic targets. However, the exact etiology has not yet been fully elucidated; thus, no drug that cures the disease has been approved. JBPOS0101 is a phenyl carbamate compound that has been tested as a drug for epileptic diseases. In our previous study, we showed that JBPOS0101 attenuated the accumulation of Aß as well as the deficits in learning and memory in the 5xFAD mouse model. Here, we tested the dose effect (70 or 35 mg/kg) of JBPOS0101 on the memory defect and pathological markers and further investigated the underlying mechanisms in 5xFAD mice. In the behavior tests, JBPOS0101 treatment ameliorated deficits in learning and memory. Moreover, JBPOS0101 attenuated Aß accumulation and tau phosphorylation. The elevated phosphorylation levels of the active GSK3ß form (GSK3ß-y216) in 5xFAD, which are responsible for tau phosphorylation, decreased in the JBPOS0101-treated groups. Furthermore, the elevation of reactive astrocytes and microglia in 5xFAD mice was attenuated in JBPOS0101-treated groups. These data suggest that JBPOS0101 may be a new drug candidate to lessen amyloid- and tau-related pathology by regulating glial cells.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas tau/metabolismo , Animais , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Memória , Camundongos , Microglia/metabolismo , Fármacos Neuroprotetores/uso terapêutico
5.
PLoS One ; 15(7): e0235543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645028

RESUMO

Senile plaques frequently contain Aß-pE(3), a N-terminally truncated Aß species that is more closely linked to AD compared to other Aß species. Tau protein is highly phosphorylated at several residues in AD, and specifically phosphorylation at Ser202/Thr205 is known to be increased in AD. Several studies suggest that formation of plaques and tau phosphorylation might be linked to each other. To evaluate if Aß-pE(3) and ptau Ser202/Thr205 levels correlate in human and transgenic AD mouse models, we analyzed human cortical and hippocampal brain tissue of different Braak stages as well as murine brain tissue of two transgenic mouse models for levels of Aß-pE(3) and ptau Ser202/Thr205 and correlated the data. Our results show that Aß-pE(3) formation is increased at early Braak stages while ptau Ser202/Thr205 mostly increases at later stages. Further analyses revealed strongest correlations between the two pathologies in the temporal, frontal, cingulate, and occipital cortex, however correlation in the hippocampus was weaker. Evaluation of murine transgenic brain tissue demonstrated a slow but steady increase of Aß-pE(3) from 6 to 12 months of age in the cortex and hippocampus of APPSL mice, and a very early and strong Aß-pE(3) increase in 5xFAD mice. ptau Ser202/Thr205 levels increased at the age of 9 months in APPSL mice and at 6 months in 5xFAD mice. Our results show that Aß-pE(3) and ptau Ser202/Thr205 levels strongly correlate in human as well as murine tissues, suggesting that tau phosphorylation might be amplified by Aß-pE(3).


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fosforilação , Ácido Pirrolidonocarboxílico/química , Especificidade da Espécie , Proteínas tau/genética
6.
Ecotoxicol Environ Saf ; 203: 110975, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32678756

RESUMO

Manganese (Mn) produces cholinergic neuronal loss in basal forebrain (BF) region that was related to cognitive dysfunction induced after single and repeated Mn treatment. All processes that generate cholinergic neuronal loss in BF remain to be understood. Mn exposure may produce the reduction of BF cholinergic neurons by increasing amyloid beta (Aß) and phosphorylated Tau (pTau) protein levels, altering heat shock proteins' (HSPs) expression, disrupting proteasome P20S activity and generating oxidative stress. These mechanisms, described to be altered by Mn in regions different than BF, could lead to the memory and learning process alteration produced after Mn exposure. The research performed shows that single and repeated Mn treatment of SN56 cholinergic neurons from BF induces P20S inhibition, increases Aß and pTau protein levels, produces HSP90 and HSP70 proteins expression alteration, and oxidative stress generation, being the last two effects mediated by NRF2 pathway alteration. The increment of Aß and pTau protein levels was mediated by HSPs and proteasome dysfunction. All these mechanisms mediated the cell decline observed after Mn treatment. Our results are relevant because they may assist to reveal the processes leading to the neurotoxicity and cognitive alterations observed after Mn exposure.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Prosencéfalo Basal/efeitos dos fármacos , Neurônios Colinérgicos/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Manganês/toxicidade , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas tau/metabolismo , Animais , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Relação Dose-Resposta a Droga , Poluentes Ambientais/metabolismo , Manganês/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos
7.
Chem Biol Interact ; 328: 109144, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32653415

RESUMO

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and ß-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3ß (GSK-3ß). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both ß-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3ß/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Excitação Neurológica/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Fosfato de Sitagliptina/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/patologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/metabolismo , Pentilenotetrazol , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/patologia , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Proteínas tau/metabolismo
8.
Life Sci ; 257: 118037, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622942

RESUMO

Palmitoylethanolamide (PEA) is an endogenous lipid mediator that, also by blunting astrocyte activation, demonstrated beneficial properties in several in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we used astrocyte-neuron co-cultures from 3xTg-AD mouse (i.e. an animal model of AD) cerebral cortex to further investigate on the role of astrocytes in PEA-induced neuroprotection. To this aim, we evaluated the number of viable cells, apoptotic nuclei, microtubule-associated protein-2 (MAP2) positive cells and morphological parameters in cortical neurons co-cultured with cortical astrocytes pre-exposed, or not, to Aß42 (0.5 µM; 24 h) or PEA (0.1 µM; 24 h). Pre-exposure of astrocytes to Aß42 failed to affect the viability, the number of neuronal apoptotic nuclei, MAP2 positive cell number, neuritic aggregations/100 µm, dendritic branches per neuron, the neuron body area, the length of the longest dendrite and number of neurites/neuron in 3xTg-AD mouse astrocyte-neuron co-cultures. Compared to neurons from wild-type (non-Tg) mouse co-cultures, 3xTg-AD mouse neurons co-cultured with astrocytes from this mutant mice displayed higher number of apoptotic nuclei, lower MAP2 immunoreactivity and several morphological changes. These signs of neuronal suffering were significantly counteracted when the 3xTg-AD mouse cortical neurons were co-cultured with 3xTg-AD mouse astrocytes pre-exposed to PEA. The present data suggest that in astrocyte-neuron co-cultures from 3xTg-AD mice, astrocytes contribute to neuronal damage and PEA, by possibly counteracting reactive astrogliosis, improved neuronal survival. These findings further support the role of PEA as a possible new therapeutic opportunity in AD treatment.


Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Etanolaminas/farmacologia , Ácidos Palmíticos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/metabolismo , Técnicas de Cocultura , Modelos Animais de Doenças , Etanolaminas/metabolismo , Gliose , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ácidos Palmíticos/metabolismo , Proteínas tau/metabolismo
10.
Proc Natl Acad Sci U S A ; 117(25): 14220-14230, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513741

RESUMO

Because raising cAMP enhances 26S proteasome activity and the degradation of cell proteins, including the selective breakdown of misfolded proteins, we investigated whether agents that raise cGMP may also regulate protein degradation. Treating various cell lines with inhibitors of phosphodiesterase 5 or stimulators of soluble guanylyl cyclase rapidly enhanced multiple proteasome activities and cellular levels of ubiquitinated proteins by activating protein kinase G (PKG). PKG stimulated purified 26S proteasomes by phosphorylating a different 26S component than is modified by protein kinase A. In cells and cell extracts, raising cGMP also enhanced within minutes ubiquitin conjugation to cell proteins. Raising cGMP, like raising cAMP, stimulated the degradation of short-lived cell proteins, but unlike cAMP, also markedly increased proteasomal degradation of long-lived proteins (the bulk of cell proteins) without affecting lysosomal proteolysis. We also tested if raising cGMP, like cAMP, can promote the degradation of mutant proteins that cause neurodegenerative diseases. Treating zebrafish models of tauopathies or Huntington's disease with a PDE5 inhibitor reduced the levels of the mutant huntingtin and tau proteins, cell death, and the resulting morphological abnormalities. Thus, PKG rapidly activates cytosolic proteasomes, protein ubiquitination, and overall protein degradation, and agents that raise cGMP may help combat the progression of neurodegenerative diseases.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Doenças Neurodegenerativas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Animais , Animais Geneticamente Modificados , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Humanos , Fosforilação , Tauopatias , Ubiquitina/metabolismo , Proteínas Ubiquitinadas/metabolismo , Ubiquitinação , Peixe-Zebra , Proteínas tau/metabolismo
11.
Nat Commun ; 11(1): 3123, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561740

RESUMO

Intracellular trafficking of organelles, driven by kinesin-1 stepping along microtubules, underpins essential cellular processes. In absence of other proteins on the microtubule surface, kinesin-1 performs micron-long runs. Under crowding conditions, however, kinesin-1 motility is drastically impeded. It is thus unclear how kinesin-1 acts as an efficient transporter in intracellular environments. Here, we demonstrate that TRAK1 (Milton), an adaptor protein essential for mitochondrial trafficking, activates kinesin-1 and increases robustness of kinesin-1 stepping on crowded microtubule surfaces. Interaction with TRAK1 i) facilitates kinesin-1 navigation around obstacles, ii) increases the probability of kinesin-1 passing through cohesive islands of tau and iii) increases the run length of kinesin-1 in cell lysate. We explain the enhanced motility by the observed direct interaction of TRAK1 with microtubules, providing an additional anchor for the kinesin-1-TRAK1 complex. Furthermore, TRAK1 enables mitochondrial transport in vitro. We propose adaptor-mediated tethering as a mechanism regulating kinesin-1 motility in various cellular environments.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Cinesina/metabolismo , Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/isolamento & purificação , Animais , Linhagem Celular Tumoral , Proteínas Intrinsicamente Desordenadas/genética , Proteínas Intrinsicamente Desordenadas/metabolismo , Cinesina/genética , Cinesina/isolamento & purificação , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Microscopia de Fluorescência , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
12.
Nat Commun ; 11(1): 3258, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591533

RESUMO

Tauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability. MTORC1 inhibition and autophagy activity are directly linked to tau clearance. Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies.


Assuntos
Autofagia , Neurônios/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Estresse Fisiológico , Tauopatias/metabolismo , Proteínas tau/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurônios/efeitos dos fármacos , Fagossomos/efeitos dos fármacos , Fagossomos/metabolismo , Fenótipo , Ratos Wistar , Estresse Fisiológico/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Tauopatias/patologia , Fatores de Tempo
13.
Gene ; 754: 144854, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32525045

RESUMO

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases. Aggregation of Aß42 and hyperphosphorylated tau are two major hallmarks of AD. Whether different forms of tau (soluble or hyperphosphorylated) or Aß are the main culprit in the events observed in AD is still under investigation. Here, we examined the effect of wild-type, prone to hyperphosphorylation and hyperphosphorylated tau, and also Aß42 peptide on the brain antioxidant defense system and two mitochondrial genes, Marf (homologous to human MFN2) and Drp1 involved in mitochondrial dynamics in transgenic Drosophila melanogaster. AD is an age associated disease. Therefore, the activity of antioxidant agents, CAT, SOD, and GSH levels and the mRNA levels of Marf and Drp1 were assessed in different time points of the flies lifespan. Reduction in cognitive function and antioxidant activity was observed in all transgenic flies at any time point. The most and the least effect on the eye phenotype was exerted by hyperphosphorylated tau and Aß42, respectively. In addition, the most remarkable alteration in Marf and Drp1 mRNA levels was observed in transgenic flies expressing hyperphosphorylated tau when pan neuronal expression of transgenes was applied. However, when the disease causing gene expression was confined to the mushroom body, Marf and Drp1 mRNA levels alteration was more prominent in tauWT and tauE14 transgenic flies, respectively. In conclusion, in spite of antioxidant deficiency caused by different types of tau and Aß42, it seems that tau exerts more toxic effect on the eye phenotype and mitochondrial genes regulation (Marf and Drp1). Moreover, different mechanisms seem to be involved in mitochondrial genes dysregulation when Aß or various forms of tau are expressed.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Animais Geneticamente Modificados/metabolismo , Drosophila melanogaster/metabolismo , Dinaminas/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , RNA Mensageiro/metabolismo , Proteínas tau/metabolismo , Animais , Animais Geneticamente Modificados/genética , Encéfalo/metabolismo , Drosophila melanogaster/genética , Dinaminas/genética , GTP Fosfo-Hidrolases/genética , Regulação da Expressão Gênica , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Fosforilação , RNA Mensageiro/genética , Proteínas tau/genética
14.
Adv Gerontol ; 33(2): 273-281, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32593241

RESUMO

The analysis of experiments and clinical data about research of neurobiological effects of chinese herbal medicine, which is used by Alzheimer`s disease treatment, was presented in given overview. The rats with injection of Aß1-42 or Aß25-35 peptides, or ibotenic acid, or streptozotocin as well as the natural line of mice SAMP8 with the phenotype of accelerated aging and other were used as the experimental models of Alzheimer`s disease. Various neurobiological effects of various herbal decoctions in the cells of hippocampus were demonstrated - the inhibition of amyloid ß peptides aggregation, increasing of neurons quantity with normal morphology and decreasing of apoptotic cells, decreasing of inducible nitric oxide synthase (iNOS) production, decreasing of reactive expression level of RAGE and increasing reactive expression level of LRP-1, decreasing of tau protein phosphorylation at Thr231 and Ser422, inhibition of expression of GSK-3ß and CDK-5, decreasing of activation and inflammation of microglia, production of 15 types of N-glycans in the cerebral cortex layers, which are absent in experimental animals. The improvement of memorization and training abilities was established.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Hipocampo/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Proteínas tau/metabolismo
15.
Neuron ; 107(3): 417-435, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32579881

RESUMO

Identifying effective treatments for Alzheimer's disease (AD) has proven challenging and has instigated a shift in AD research focus toward the earliest disease-initiating cellular mechanisms. A key insight has been an increase in soluble Aß oligomers in early AD that is causally linked to neuronal and circuit hyperexcitability. However, other accumulating AD-related peptides and proteins, including those derived from the same amyloid precursor protein, such as Aη or sAPPα, and autonomously, such as tau, exhibit surprising opposing effects on circuit dynamics. We propose that the effects of these on neuronal circuits have profound implications for our understanding of disease complexity and heterogeneity and for the development of personalized diagnostic and therapeutic strategies in AD. Here, we highlight important peptide-specific mechanisms of dynamic pathological disequilibrium of cellular and circuit activity in AD and discuss approaches in which these may be further understood, and theoretically and experimentally leveraged, to elucidate AD pathophysiology.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Convulsões/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Astrócitos/metabolismo , Segmento Inicial do Axônio/metabolismo , Encéfalo/fisiopatologia , Humanos , Microglia/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Vias Neurais , Fragmentos de Peptídeos/metabolismo , Receptores de Glutamato/metabolismo , Convulsões/fisiopatologia , Sinapses/metabolismo
16.
Neurology ; 95(2): e155-e165, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32561678

RESUMO

OBJECTIVE: To determine whether Lewy body disease subgroups have different clinical profiles. METHODS: Participants had dementia, autopsy-confirmed transitional or diffuse Lewy body disease (TLBD or DLBD) (n = 244), or Alzheimer disease (AD) (n = 210), and were seen at least twice (mean follow-up 6.2 ± 3.8 years). TLBD and DLBD groups were partitioned based on the presence or absence of neocortical neurofibrillary tangles using Braak staging. Four Lewy body disease subgroups and AD were compared on clinical features, dementia trajectory, and onset latency of probable dementia with Lewy bodies (DLB) or a DLB syndrome defined as probable DLB or dementia with one core feature of parkinsonism or probable REM sleep behavior disorder. RESULTS: In TLBD and DLBD without neocortical tangles, diagnostic sensitivity was strong for probable DLB (87% TLBD, 96% DLBD) and the DLB syndrome (97% TLBD, 98% DLBD) with median latencies <1 year from cognitive onset, and worse baseline attention-visual processing but better memory-naming scores than AD. In DLBD with neocortical tangles, diagnostic sensitivity was 70% for probable DLB and 77% for the DLB syndrome with respective median latencies of 3.7 years and 2.7 years from cognitive onset, each associated with tangle distribution. This group had worse baseline attention-visual processing than AD, but comparable memory-naming impairment. TLBD with neocortical tangles had 48% diagnostic sensitivity for probable DLB and 52% for the DLB syndrome, with median latencies >6 years from cognitive onset, and were cognitively similar to AD. Dementia trajectory was slowest for TLBD without neocortical tangles, and fastest for DLBD with neocortical tangles. CONCLUSIONS: The phenotypic expression of DLB was associated with the distribution of α-synuclein and tau pathology.


Assuntos
Doença por Corpos de Lewy/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Atenção , Cognição , Progressão da Doença , Feminino , Humanos , Doença por Corpos de Lewy/classificação , Doença por Corpos de Lewy/psicologia , Masculino , Memória , Pessoa de Meia-Idade , Neocórtex/patologia , Emaranhados Neurofibrilares/patologia , Desempenho Psicomotor , Sensibilidade e Especificidade
17.
Lancet ; 395(10242): 1988-1997, 2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32593336

RESUMO

BACKGROUND: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. METHODS: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid ß peptides 1-42 and 1-40 and their ratio (Aß1-42/1-40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. FINDINGS: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aß1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life. INTERPRETATION: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. FUNDING: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.


Assuntos
Doença de Alzheimer/metabolismo , Biomarcadores/sangue , Síndrome de Down/complicações , Adulto , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/diagnóstico por imagem , Amiloidose/patologia , Apolipoproteínas E/metabolismo , Estudos de Casos e Controles , Disfunção Cognitiva/psicologia , Estudos Transversais , Síndrome de Down/epidemiologia , Síndrome de Down/mortalidade , Síndrome de Down/psicologia , Fluordesoxiglucose F18/administração & dosagem , Humanos , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Prevalência , Espanha/epidemiologia , Reino Unido/epidemiologia , Proteínas tau/metabolismo
18.
Neurology ; 94(21): e2233-e2244, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32398359

RESUMO

OBJECTIVE: To compare different ß-amyloid (Aß), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies. METHODS: A total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aß42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation. RESULTS: Among CU participants, A-T-(N)- or A+T-(N)- variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures. CONCLUSIONS: Our findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.


Assuntos
Doença de Alzheimer/classificação , Doença de Alzheimer/epidemiologia , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/epidemiologia , Degeneração Neural/epidemiologia , Proteínas tau/metabolismo , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina/metabolismo , Benzotiazóis/metabolismo , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Carbolinas/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes de Estado Mental e Demência/estatística & dados numéricos , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Suécia/epidemiologia , Proteínas tau/líquido cefalorraquidiano
19.
PLoS One ; 15(5): e0221669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437347

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies. Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intracellular soluble amyloid precursor protein (sAPPf) fragments and extracellular Aß42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation provide important clues for the identification of targetable pathological molecules.


Assuntos
Doença de Alzheimer , Neurônios Colinérgicos , Células-Tronco Mesenquimais , Presenilina-1 , Cordão Umbilical , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Apoptose , Ácido Aspártico Endopeptidases/metabolismo , Cálcio/metabolismo , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Mutação , Estresse Oxidativo , Presenilina-1/genética , Presenilina-1/metabolismo , Cordão Umbilical/metabolismo , Cordão Umbilical/patologia , Proteínas tau/metabolismo
20.
Adv Exp Med Biol ; 1195: 19, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468453

RESUMO

Over 40 million people worldwide suffer from dementia. This number is projected to exceed 110 million by 2050 because of the aging of the worldwide population, especially in lower- and middle-income countries. The most common cause of dementia is believed to be Alzheimer's, a brain disease associated with deposition of beta-amyloid protein and hyperphosphorylation of intraneuronal tau protein leading to synaptic degradation, neuronal loss, brain circuit disruption, a range of symptoms, and eventually, if the person lives long enough, death. Over the last few decades, treatment development has focused on the deposition of beta-amyloid protein (A-beta 1-42) that is produced in the brain in huge quantities continuously and is thought to be toxic. Unfortunately, amyloid oriented therapies targeting individuals with dementia, or its prodrome mild cognitive impairment (MCI), have not been successful therapeutically even though they have been associated with reductions in amyloid. Currently, efforts are underway to deliver these therapies to individuals with very early symptoms or at risk for Alzheimer's dementia by virtue of genetics or a brain amyloid PET scan. Results from these studies are expected to begin to emerge by early 2020. In the meantime, since the amyloid hypothesis has been called into question, a number of different avenues are being pursued for treatment development. These are driven in part by new findings related to the polygenic nature of Alzheimer's as well as the interaction between this brain disease with factors such as brain vascular disease, insulin resistance, and/or brain inflammation. The expected future of AD treatment development is thought to be precision medicine.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Doença de Alzheimer/patologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Humanos , Tomografia por Emissão de Pósitrons , Medicina de Precisão , Proteínas tau/metabolismo
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