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1.
FASEB J ; 34(2): 2968-2977, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908108

RESUMO

Tau hyperphosphorylation is a major neuropathological hallmark of many neurodegenerative disorders such as Alzheimer's disease. Several anesthetics have been shown previously to induced marked tau hyperphosphorylation. Although the ketamine/xylazine mixture is one of the most commonly used anesthetic agents in animal research and veterinary practice, the effect of this anesthetic agent on tau phosphorylation still remains to be determined. Here, we found that ketamine-/xylazine-induced a rapid and robust hyperphosphorylation of tau in a dose-dependent manner under normothermic and hypothermic conditions in mice. When used together, ketamine and xylazine exerted a synergistic action on tau phosphorylation most strongly not only on epitopes S396 and S262, but also on other residues (T181, and S202/T205). We observed that activation of the calmodulin-dependent protein kinase II (CaMKII) is the major upstream molecular event leading to tau hyperphosphorylation following ketamine/xylazine anesthesia in mice. Moreover, we observed that intracerebroventricular injection of the selective CaMKII inhibitor KN93 attenuated tau hyperphosphorylation. Since ketamine/xylazine also had a marked impact on other key molecular signaling pathways involving the MAP/microtubule affinity-regulating kinase (MARK), extracellular signal-regulated kinase (ERK), and glycogen synthase kinase-3 (GSK3), our study calls for high caution and careful monitoring when using this anesthetic agent in laboratory animal settings across all fields of biological sciences in order to avoid artifactual results.


Assuntos
Anestésicos Dissociativos/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ketamina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Xilazina/farmacologia , Proteínas tau/metabolismo , Anestésicos Dissociativos/efeitos adversos , Animais , Ketamina/efeitos adversos , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Xilazina/efeitos adversos
2.
Neurobiol Learn Mem ; 160: 108-117, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29908972

RESUMO

Alzheimer's disease (AD) is a debilitating neurodegenerative disease characterized by progressive hippocampal-dependent explicit memory deficits that begin at the onset of the illness. An early hallmark of AD is the accumulation of amyloid-beta (Aß) proteins in brain structures involved in encoding and consolidation of memory, like the hippocampus and prefrontal cortex. Aß neurotoxicity is known to induce synaptic dysfunctions and neuronal death leading to cognitive decline. Another recurrent event observed in AD is sleep disturbances. Decreased sleep duration, sleep fragmentation, and circadian alterations are often observed in early AD. The origin of these disturbances, and especially the specific contribution of the hippocampal Aß pathology, remains to be determined. It is required to identify mechanisms impacting wakefulness and sleep architecture and microarchitecture given the role of sleep in memory encoding and consolidation. Sleep perturbations in AD are thus likely contributing to memory decline in the course of the disease. The central aim of this review is to address the bidirectional relationship between sleep and hippocampal Aß by discussing the literature featuring data on wakefulness and sleep variables (i.e., duration, electroencephalographic activity, daily distribution) in AD mouse models and on the effect of enforced sleep loss on Aß pathology in the hippocampus. The current state of knowledge on this topic emphasizes a clear need for more efforts to assess the precise impact of hippocampal Aß on wakefulness and sleep quality as well as the mechanisms mediating their reciprocal relationship.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Hipocampo , Privação do Sono , Sono , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Camundongos , Sono/fisiologia , Privação do Sono/metabolismo , Privação do Sono/patologia , Privação do Sono/fisiopatologia
3.
Int J Mol Sci ; 19(12)2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30486235

RESUMO

Myocardial infarction (MI) in animal models induces cognitive deficits as well as the activation of caspase in the limbic system; both can be blocked by 2 weeks of treatment following MI using tricyclic antidepressants or selective serotonin uptake blockers. Here we used three different treatment schedules to test the short- and long-term effects of the combined serotonin-norepinephrine reuptake inhibitor desvenlafaxine on post-MI-associated cognitive deficits and caspase activation. MI was induced in 39 young adult rats, and 39 rats served as sham-operated controls. Desvenlafaxine (3 mg/kg/day, i.p.) or saline was administered according to one of three schedules: (1) for 2 weeks, starting right after surgery; (2) for 16 weeks, starting 2 weeks after surgery; (3) for 16 weeks, starting right after surgery. Behavior was tested 2 weeks (social interaction, passive avoidance) and 16 weeks (forced swimming, Morris water maze) after surgery. Caspase-3 and caspase-6 activities were measured 16 weeks after surgery. At 2 and 16 weeks post-surgery, saline-treated MI rats displayed performance deficits compared to desvenlafaxine-treated rats, regardless of the treatment schedule. Caspase-3 activity was higher in the amygdala (medial and lateral) and hippocampal CA3 region in untreated MI rats, whereas caspase-6 activity was higher in the CA1 region. Caspase-6 activity correlated positively with deficits in the Morris water maze. These results indicate that, independently of treatment schedules, various treatment schedules with desvenlafaxine can prevent MI-associated cognitive deficits and decrease caspase activities in the limbic system.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Succinato de Desvenlafaxina/uso terapêutico , Infarto do Miocárdio/complicações , Norepinefrina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Animais , Aprendizagem da Esquiva , Comportamento Animal/efeitos dos fármacos , Caspases/metabolismo , Cicatriz/patologia , Transtornos Cognitivos/patologia , Succinato de Desvenlafaxina/farmacologia , Masculino , Aprendizagem em Labirinto , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Comportamento Social , Memória Espacial , Natação
4.
PLoS Biol ; 12(8): e1001923, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25093460

RESUMO

STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/enzimologia , Inibidores Enzimáticos/uso terapêutico , Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Animais , Benzotiepinas/farmacologia , Benzotiepinas/uso terapêutico , Domínio Catalítico , Morte Celular/efeitos dos fármacos , Córtex Cerebral/patologia , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Cisteína/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/química , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Especificidade por Substrato/efeitos dos fármacos
5.
J Neurosci ; 32(23): 7852-61, 2012 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-22674261

RESUMO

Neuronal and synaptic degeneration are the best pathological correlates for memory decline in Alzheimer's disease (AD). Although the accumulation of soluble low-molecular-weight amyloid-ß (Aß) oligomers has been suggested to trigger neurodegeneration in AD, animal models overexpressing or infused with Aß lack neuronal loss at the onset of memory deficits. Using a novel in vivo approach, we found that repeated hippocampal injections of small soluble Aß(1-42) oligomers in awake, freely moving mice were able to induce marked neuronal loss, tau hyperphosphorylation, and deficits in hippocampus-dependent memory. The neurotoxicity of small Aß(1-42) species was observed in vivo as well as in vitro in association with increased caspase-3 activity and reduced levels of the NMDA receptor subunit NR2B. We found that the sequestering agent transthyretin is able to bind the toxic Aß(1-42) species and attenuated the loss of neurons and memory deficits. Our novel mouse model provides evidence that small, soluble Aß(1-42) oligomers are able to induce extensive neuronal loss in vivo and initiate a cascade of events that mimic the key neuropathological hallmarks of AD.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Transtornos da Memória/induzido quimicamente , Síndromes Neurotóxicas/psicologia , Fragmentos de Peptídeos/toxicidade , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/química , Animais , Aprendizagem da Esquiva , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Feminino , Formiatos/farmacologia , Hipocampo , Imuno-Histoquímica , Injeções , Isomerismo , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/patologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Peso Molecular , Neurônios/patologia , Síndromes Neurotóxicas/patologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/química , Fosforilação , Pré-Albumina/farmacologia , Proteínas tau/metabolismo
6.
Front Cell Neurosci ; 17: 1208122, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37388411

RESUMO

The role of non-neuronal cells has been relatively overlooked in Alzheimer's disease (AD) neuropathogenesis compared to neuronal cells since the first characterization of the disease. Genome wide-association studies (GWAS) performed in the last few decades have greatly contributed to highlighting the critical impact of non-neuronal cells in AD by uncovering major genetic risk factors that are found largely in these cell types. The recent development of single cell or single nucleus technologies has revolutionized the way we interrogate the transcriptomic and epigenetic profiles of neurons, microglia, astrocytes, oligodendrocytes, pericytes, and endothelial cells simultaneously in the same sample and in an individual manner. Here, we review the latest advances in single-cell/nucleus RNA sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to more accurately understand the function of non-neuronal cells in AD. We conclude by giving an overview of what still needs to be achieved to better appreciate the interconnected roles of each cell type in the context of AD.

7.
Alzheimers Res Ther ; 15(1): 174, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37833786

RESUMO

BACKGROUND: Soluble amyloid-beta oligomers (Aßo) begin to accumulate in the human brain one to two decades before a clinical diagnosis of Alzheimer's disease (AD). The literature supports that soluble Aßo are implicated in synapse and neuronal losses in the brain regions such as the hippocampus. This region importantly contributes to explicit memory, the first type of memory affected in AD. During AD preclinical and prodromal stages, people are also experiencing wake/sleep alterations such as insomnia (e.g., difficulty initiating sleep, decreased sleep duration), excessive daytime sleepiness, and sleep schedule modifications. In addition, changes in electroencephalographic (EEG) activity during wake and sleep have been reported in AD patients and animal models. However, the specific contribution of Aßo to wake/sleep alterations is poorly understood and was investigated in the present study. METHODS: Chronic hippocampal injections of soluble Aßo were conducted in male rats and combined with EEG recording to determine the progressive impact of Aß pathology specifically on wake/sleep architecture and EEG activity. Bilateral injections were conducted for 6 consecutive days, and EEG acquisition was done before, during, and after Aßo injections. Immunohistochemistry was used to assess neuron numbers in the hippocampal dentate gyrus (DG). RESULTS: Aßo injections did not affect the time spent in wakefulness, slow wave sleep (SWS), and paradoxical sleep but altered EEG activity during wake and SWS. More precisely, Aßo increased slow-wave activity (SWA; 0.5-5 Hz) and low-beta activity (16-20 Hz) during wake and decreased theta (5-9 Hz) and alpha (9-12 Hz) activities during SWS. Moreover, the theta activity/SWA ratio during wake and SWS was decreased by Aßo. These effects were significant only after 6 days of Aßo injections and were found with alterations in neuron counts in the DG. CONCLUSIONS: We found multiple modifications of the wake and SWS EEG following Aßo delivery to the hippocampus. These findings expose a specific EEG signature of Aß pathology and can serve the development of non-invasive and cost-effective markers for the early diagnosis of AD or other amyloid-related diseases.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Sono de Ondas Lentas , Animais , Humanos , Masculino , Ratos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Eletroencefalografia , Hipocampo/patologia , Sono/fisiologia
8.
Front Neurosci ; 17: 1219299, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37483337

RESUMO

Propagation of tau fibrils correlate closely with neurodegeneration and memory deficits seen during the progression of Alzheimer's disease (AD). Although it is not well-established what drives or attenuates tau spreading, new studies on human brain using positron emission tomography (PET) have shed light on how tau phosphorylation, genetic factors, and the initial epicenter of tau accumulation influence tau accumulation and propagation throughout the brain. Here, we review the latest PET studies performed across the entire AD continuum looking at the impact of amyloid load on tau pathology. We also explore the effects of structural, functional, and proximity connectivity on tau spreading in a stereotypical manner in the brain of AD patients. Since tau propagation can be quite heterogenous between individuals, we then consider how the speed and pattern of propagation are influenced by the starting localization of tau accumulation in connected brain regions. We provide an overview of some genetic variants that were shown to accelerate or slow down tau spreading. Finally, we discuss how phosphorylation of certain tau epitopes affect the spreading of tau fibrils. Since tau pathology is an early event in AD pathogenesis and is one of the best predictors of neurodegeneration and memory impairments, understanding the process by which tau spread from one brain region to another could pave the way to novel therapeutic avenues that are efficient during the early stages of the disease, before neurodegeneration induces permanent brain damage and severe memory loss.

9.
Anesthesiology ; 116(4): 779-87, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22343471

RESUMO

BACKGROUND: There is a growing interest in the involvement of anesthetic agents in the etiology of postoperative cognitive dysfunction. Recent animal studies suggest that acute anesthesia induces transient hyperphosphorylation of tau, an effect essentially ascribed to hypothermia. The main aim of the present study was to investigate effects, in normothermic conditions, of acute or repeated exposure to sevoflurane, a halogenated anesthetic agent, on hippocampal tau phosphorylation and spatial memory in adult mice. METHODS: 5 to 6-month-old C57Bl6/J mice were submitted to acute (1 h) or repeated (five exposures of 1h every month) anesthesia using 1.5 or 2.5% sevoflurane, in normothermic conditions. In the acute protocol, animals were sacrificed 1 and 24 h after exposure. In the chronic protocol, spatial memory was evaluated using the Morris water maze following the fourth exposure, and tau phosphorylation evaluated 1 month following the last exposure using bi- and mono-dimensional electrophoresis. RESULTS: Acute sevoflurane anesthesia in normothermic conditions led to a significant dose-dependent and reversible hippocampal tau phosphorylation, 1 h following the end of exposure (P < 0.001). Conversely, repeated anesthesia led to persistent tau hyperphosphorylation and significant memory impairments, as seen in the retention phase of the Morris water maze in sevoflurane-anesthesized animals. These pathologic features may be related to the activation of both Akt and Erk pathways. CONCLUSIONS: The present study demonstrates, in mice, that sevoflurane exposure is associated with increased tau phosphorylation through specific kinases activation and spatial memory deficits. These data support a correlation between exposures to this anesthetic agent and cognitive decline.


Assuntos
Anestesia Geral/efeitos adversos , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Éteres Metílicos/efeitos adversos , Proteínas tau/metabolismo , Doença Aguda , Animais , Doença Crônica , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/fisiologia , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/metabolismo , Sevoflurano
10.
J Neurosci ; 30(38): 12690-700, 2010 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-20861374

RESUMO

High levels of reactive oxygen species (ROS) are associated with deficits in learning and memory with age as well as in Alzheimer's disease. Using DNA microarray, we demonstrated the overexpression of quinone reductase 2 (QR2) in the hippocampus in two models of learning deficits, namely the aged memory impaired rats and the scopolamine-induced amnesia model. QR2 is a cytosolic flavoprotein that catalyzes the reduction of its substrate and enhances the production of damaging activated quinone and ROS. QR2-like immunostaining is enriched in cerebral structures associated with learning behaviors, such as the hippocampal formation and the temporofrontal cortex of rat, mouse, and human brains. In cultured rat embryonic hippocampal neurons, selective inhibitors of QR2, namely S26695 and S29434, protected against menadione-induced cell death by reversing its proapoptotic action. S26695 (8 mg/kg) also significantly inhibited scopolamine-induced amnesia. Interestingly, adult QR2 knock-out mice demonstrated enhanced learning abilities in various tasks, including Morris water maze, object recognition, and rotarod performance test. Other behaviors related to anxiety (elevated plus maze), depression (forced swim), and schizophrenia (prepulse inhibition) were not affected in QR2-deficient mice. Together, these data suggest a role for QR2 in cognitive behaviors with QR2 inhibitors possibly representing a novel therapeutic strategy toward the treatment of learning deficits especially observed in the aged brain.


Assuntos
Hipocampo/metabolismo , Aprendizagem/fisiologia , Neurônios/metabolismo , Quinona Redutases/metabolismo , Reconhecimento Psicológico/fisiologia , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Hipocampo/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Piridinas/farmacologia , Alcaloides de Pirrolizidina/farmacologia , Quinona Redutases/antagonistas & inibidores , Quinona Redutases/genética , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Teste de Desempenho do Rota-Rod , Natação
11.
Neurodegener Dis ; 7(1-3): 88-95, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20173334

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss, possibly triggered by the accumulation of beta-amyloid (Abeta) peptides and the hyperphosphorylation of Tau neurofilament protein. Recent findings have shown that transthyretin (TTR) is a potent scavenger of Abeta peptide deposits, suggesting a possible neuroprotective role for TTR in neurodegenerative processes associated with amyloidogenesis, such as AD. METHODS: To investigate the relationship between TTR and Abeta deposition, we crossed mouse carrying a deletion of TTR (TTR(- or -)) with a transgenic mouse model of AD (TgCRND8), and Abeta burden and spatial learning capacities were evaluated at 4 and 6 months of age (exclusion of the 6 month-old TgCRND8/TTR(- or -) group due to low survival rate). RESULTS: Rather surprisingly, Abeta plaque burden was significantly reduced in the hippocampus of 4-month-old TgCRND8/TTR(+ or -), and to a lesser extent in TgCRND8/TTR(- or -), as compared to age-matched TgCRND8/TTR(+ or +). No difference in plaque burden was found between any groups in 6-month-old animals. At 4 and 6 months of age, all populations of these hybrid transgenic mice displayed similar magnitude of spatial memory deficits in the Morris water maze task. CONCLUSION: Since TgCRND8 mice represent an aggressive model of Abeta deposition with plaques developing as early as 3 months of age, along with spatial learning deficits, it may be already too late at 4 and 6 months of age to observe significant changes due to the deletion of the TTR gene.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Deficiências da Aprendizagem/etiologia , Pré-Albumina/metabolismo , Fatores Etários , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pré-Albumina/deficiência
12.
Front Mol Neurosci ; 13: 600084, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33488358

RESUMO

Soluble amyloid-beta oligomers (Aßo) start to accumulate in the human brain one to two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated in synapse loss, one of the best predictors of memory decline that characterize the illness. Cognitive impairment in AD was traditionally thought to result from a reduction in synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates that in the early stages of AD synaptic failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review the growing body of evidence supporting the implication of soluble Aßo on the induction of neuronal hyperactivity in AD animal models, in vitro, and in humans. We then discuss the impact of Aßo-induced hyperactivity on memory performance, cell death, epileptiform activity, gamma oscillations, and slow wave activity. We provide an overview of the cellular and molecular mechanisms that are emerging to explain how Aßo induce neuronal hyperactivity. We conclude by providing an outlook on the impact of hyperactivity for the development of disease-modifying interventions at the onset of AD.

13.
Sci Rep ; 10(1): 6956, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332783

RESUMO

Synapse loss occurs early and correlates with cognitive decline in Alzheimer's disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (Aßo), but the exact synaptic components targeted by Aßo remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by Aßo, and that it can modulate Aßo toxicity. We found that hippocampal NLGN1 was decreased in patients with AD in comparison to patients with mild cognitive impairment and control subjects. Female 3xTg-AD mice also showed a decreased NLGN1 level in the hippocampus at an early age (i.e., 4 months). We observed that chronic hippocampal Aßo injections initially increased the expression of one specific Nlgn1 transcript, which was followed by a clear decrease. Lastly, the absence of NLGN1 decreased neuronal counts in the dentate gyrus, which was not the case in wild-type animals, and worsens impairment in spatial learning following chronic hippocampal Aßo injections. Our findings support that NLGN1 is impacted early during neurodegenerative processes, and that Aßo contributes to this effect. Moreover, our results suggest that the presence of NLGN1 favors the cognitive prognosis during Aßo-driven neurodegeneration.


Assuntos
Doença de Alzheimer/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Hipocampo/metabolismo , Envelhecimento/genética , Envelhecimento/fisiologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Western Blotting , Moléculas de Adesão Celular Neuronais/genética , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Teste do Labirinto Aquático de Morris
14.
Neurobiol Dis ; 35(3): 406-14, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19524673

RESUMO

Cerebrovascular dysfunctions appear to contribute to Alzheimer's disease (AD) pathogenesis and the associated cognitive decline. Recently, it has been suggested that statins could be beneficial to AD patients independently from their cholesterol-lowering effects. Using 10 month-old amyloid precursor protein transgenic mice (APP mice), we sought to reverse cerebrovascular, neuronal and memory impairments with simvastatin (20 mg/kg/day, 8 weeks). Simvastatin improved reactivity of cerebral arteries, rescued the blood flow response to neuronal activation, attenuated oxidative stress and inflammation, and reduced cortical soluble amyloid-beta (Abeta) levels and the number of Abeta plaque-related dystrophic neurites. However, at such an advanced stage of the pathology, it failed to reduce Abeta plaque load and normalize cholinergic and memory deficits. These findings demonstrate that low-dose simvastatin treatment in aged APP mice largely salvages cerebrovascular function and has benefits on several AD landmarks, which could explain some of the positive effects of statins reported in AD patients.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Encefalite/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Sinvastatina/uso terapêutico , Envelhecimento , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Modelos Animais de Doenças , Humanos , Deficiências da Aprendizagem/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroimunomodulação/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/administração & dosagem , Placa Amiloide/efeitos dos fármacos , Nexinas de Proteases , Receptores de Superfície Celular/genética , Sinvastatina/administração & dosagem , Percepção Espacial/efeitos dos fármacos
15.
Neurotoxicology ; 29(2): 318-27, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18294692

RESUMO

Many toxic environmental and food agents have been suspected to be potential risk factors in inducing memory disabilities under normal and pathological conditions. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (known as dioxin or TCDD) is a common and prototypical member of a class of noxious environmental and food contaminants called the halogenated aromatic hydrocarbons. Since the role of dioxin in memory processes has not been studied in detail, the present report aims at elucidating the role of this pollutant in the maintenance of cognitive function. We found that TCDD (50miccrog/kg) induced spatial memory deficits in the Morris water maze (MWM) task in female but not male mice. This sex-dependant effect of dioxin seems to be related to the alteration of estrogen pathways, as treatment with 17beta-estradiol-3-benzoate (E; 5microg/day) reversed memory deficits induced by TCDD. We also observed that cognitive impairments produced by dioxin, which is known to interfere with retinoid turnover and metabolism, were abolished by retinoic acid (RA) treatment (150microg/kg). The cognitive effects of E and RA treatments seem to derive from common rather than additive mechanisms since memory deficits produced by TCDD were fully reversed by these compounds when used separately or in combination. Attenuation of dioxin-induced memory deficits in mice lacking transthyretin (TTR) suggests that TCDD may be acting by affecting the major route of retinol transport involving TTR. Taken together, these results suggest that the environmental and food pollutant TCDD can induce memory deficits by altering the estrogen pathways and a main route of TTR-mediated retinol transport.


Assuntos
Poluentes Ambientais/toxicidade , Estrogênios/metabolismo , Transtornos da Memória/induzido quimicamente , Memória/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Pré-Albumina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vitamina A/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Cognição/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pré-Albumina/deficiência , Pré-Albumina/genética , Fatores Sexuais , Tretinoína/farmacologia
16.
Curr Biol ; 28(7): 1079-1089.e4, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29576474

RESUMO

Cognitive disabilities that occur with age represent a growing and expensive health problem. Age-associated memory deficits are observed across many species, but the underlying molecular mechanisms remain to be fully identified. Here, we report elevations in the levels and activity of the striatal-enriched phosphatase (STEP) in the hippocampus of aged memory-impaired mice and rats, in aged rhesus monkeys, and in people diagnosed with amnestic mild cognitive impairment (aMCI). The accumulation of STEP with aging is related to dysfunction of the ubiquitin-proteasome system that normally leads to the degradation of STEP. Higher level of active STEP is linked to enhanced dephosphorylation of its substrates GluN2B and ERK1/2, CREB inactivation, and a decrease in total levels of GluN2B and brain-derived neurotrophic factor (BDNF). These molecular events are reversed in aged STEP knockout and heterozygous mice, which perform similarly to young control mice in the Morris water maze (MWM) and Y-maze tasks. In addition, administration of the STEP inhibitor TC-2153 to old rats significantly improved performance in a delayed alternation T-maze memory task. In contrast, viral-mediated STEP overexpression in the hippocampus is sufficient to induce memory impairment in the MWM and Y-maze tests, and these cognitive deficits are reversed by STEP inhibition. In old LOU/C/Jall rats, a model of healthy aging with preserved memory capacities, levels of STEP and GluN2B are stable, and phosphorylation of GluN2B and ERK1/2 is unaltered. Altogether, these data suggest that elevated levels of STEP that appear with advancing age in several species contribute to the cognitive declines associated with aging.


Assuntos
Hipocampo/metabolismo , Transtornos da Memória/fisiopatologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Tirosina/metabolismo , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Ratos , Ratos Sprague-Dawley
17.
Br J Pharmacol ; 148(1): 25-38, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16491095

RESUMO

1 Effects of intrathecally (i.t.) injected tachykinin NK-1 and -3 receptor agonists and antagonists were measured on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR,15-week-old) and age-matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiography was also performed on the lower thoracic spinal cord of both strains and Wistar rats using specific radioligands for NK-1 receptor ([(125)I]HPP[Arg(3),Sar(9),Met(O(2))(11)]SP (3-11)) and NK-3 receptor ([(125)I]HPP-Asp-Asp-Phe-N-MePhe-Gly-Leu-Met-NH(2)). 2 The NK-1 agonist [Sar(9),Met(O(2))(11)]SP (650 and 6500 pmol) decreased MAP and increased HR in WKY. The fall in MAP was blunted in SHR and substituted by increases in MAP (65-6500 pmol) and more sustained tachycardia. The NK-3 agonist senktide (6.5-65 pmol) evoked marked increases in MAP and HR (SHR>>>WKY), yet this response was rapidly desensitized. Cardiovascular effects of [Sar(9),Met(O(2))(11)]SP (650 pmol) and senktide (6.5 pmol) were selectively blocked by the prior i.t. injection of LY303870 (NK-1 antagonist, 65 nmol) and SB235375 (NK-3 antagonist, 6.5 nmol), respectively. Antagonists had no direct effect on MAP and HR in both strains. 3 Densities of NK-1 and -3 receptor binding sites were significantly increased in all laminae of the spinal cord in SHR when compared to control WKY and Wistar rats. The dissociation constant was however not affected in SHR for both NK-1 (K(d)=2.5 nM) and NK-3 (K(d)=5 nM) receptors. 4 Data highlight an upregulation of NK-1 and -3 receptor binding sites in the thoracic spinal cord of SHR that may contribute to the hypersensitivity of the pressor response to agonists and to the greater sympathetic activity seen in this model of arterial hypertension.


Assuntos
Acetatos/farmacologia , Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea , Hipertensão/fisiopatologia , Indóis/farmacologia , Fragmentos de Peptídeos/farmacologia , Piperidinas/farmacologia , Quinolinas/farmacologia , Receptores da Neurocinina-1/biossíntese , Receptores da Neurocinina-3/biossíntese , Medula Espinal/efeitos dos fármacos , Substância P/análogos & derivados , Regulação para Cima , Acetatos/administração & dosagem , Animais , Autorradiografia , Relação Dose-Resposta a Droga , Frequência Cardíaca , Indóis/administração & dosagem , Injeções Espinhais , Masculino , Fragmentos de Peptídeos/administração & dosagem , Piperidinas/administração & dosagem , Quinolinas/administração & dosagem , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Wistar , Receptores da Neurocinina-1/análise , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-3/análise , Receptores da Neurocinina-3/efeitos dos fármacos , Medula Espinal/metabolismo , Substância P/administração & dosagem , Substância P/farmacologia , Vértebras Torácicas
18.
J Vis Exp ; (114)2016 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-27585306

RESUMO

Decline in hippocampal-dependent explicit memory (memory for facts and events) is one of the earliest clinical symptom of Alzheimer's disease (AD). It is well established that synapse loss and ensuing neurodegeneration are the best predictors for memory impairments in AD. Latest studies have emphasized the neurotoxic role of soluble amyloid-beta oligomers (Aßo) that begin to accumulate in the human brain approximately 10 to 15 yr before the clinical symptoms become apparent. Many reports indicate that soluble Aßo correlate with memory deficits in AD models and humans. The Aßo-induced neurodegeneration observed in neuronal and brain slice cultures has been more challenging to reproduce in many animal models. The model of repeated Aßo infusions shown here overcome this issue and allow addressing two key domains for developing new disease modifying therapies: identify biological markers to diagnose early AD, and determine the molecular mechanisms underpinning Aßo-induced memory deficits at the onset of AD. Since soluble Aßo aggregate relatively fast into insoluble Aß fibrils that correlate poorly with the clinical state of patients, soluble Aßo are prepared freshly and injected once per day during six days to produce marked cell death in the hippocampus. We used cannula specially design for simultaneous infusions of Aßo and continuous infusion of Aßo antibody (6E10) in the hippocampus using osmotic pumps. This innovative in vivo method can now be used in preclinical studies to validate the efficiency of new AD therapies that might prevent the deposition and neurotoxicity of Aßo in pre-dementia patients.


Assuntos
Doença de Alzheimer/terapia , Modelos Animais de Doenças , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/efeitos adversos , Animais , Hipocampo , Humanos , Transtornos da Memória , Neurônios
19.
Br J Pharmacol ; 136(8): 1169-77, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12163350

RESUMO

1 The activation of tachykinin NK(1) receptors in the rat spinal cord produced a transient drop in arterial blood pressure followed by a more prolonged pressor effect which is mediated by the stimulation of the sympatho-adrenal system. This study aims at characterizing the spinal mechanism of that initial hypotension occurring in awake unrestrained rats. 2 The initial hypotension (-18+/-2.0 mmHg at 1 min) and the tachycardia (110+/-10 b.p.m.) produced by the intrathecal (i.t.) injection of the stable NK(1) receptor agonist [Sar(9), Met(O(2))(11)]-SP (Sar9, 0.65 nmol) at T-9 spinal cord level was inhibited by the prior injection of 65 nmol LY306740 or LY303870 (NK(1) receptor antagonists). No inhibition was seen when a similar dose of antagonists was given intravenously. 3 The prior i.t. injection of the GABA(B) receptor antagonist CGP52432 (100 nmol) reduced the hypotension evoked by Sar9 (0.65 nmol) and by the GABA(B) receptor agonist baclofen (100 nmol). The GABA(A) receptor antagonist bicuculline (25 nmol, i.t.) was without effect against Sar9, and the GABA(A) agonist muscimol (100 nmol, i.t.) had no cardiovascular effect. 4 The putative involvement of other mediators (dopamine, serotonine, glycine and glutamate) in Sar9-induced hypotension was made unlikely on the basis of various pharmacological treatments. Thus data, suggest that the transient hypotension which occurs upon the activation of NK(1) receptors in the spinal cord is due to the release of GABA which in turn activates GABA(B) receptors to inhibit sympathetic pre-ganglionic fibres. This mechanism may have a physiological significance in the spinal reflex autonomic control of arterial blood pressure.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Células do Corno Posterior/efeitos dos fármacos , Receptores de GABA-B/fisiologia , Substância P/análogos & derivados , Substância P/farmacologia , Substância P/fisiologia , Vasoconstritores/farmacologia , Animais , Benzilaminas/farmacologia , Bicuculina/farmacologia , Depressão Química , Relação Dose-Resposta a Droga , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Injeções Intravenosas , Injeções Espinhais , Masculino , Ácidos Fosfínicos/farmacologia , Células do Corno Posterior/metabolismo , Ratos , Ratos Wistar , Receptores da Neurocinina-1/efeitos dos fármacos , Vigília , Ácido gama-Aminobutírico/metabolismo
20.
Curr Pharm Des ; 20(15): 2506-19, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23859546

RESUMO

The neurodegenerative process that defines Alzheimer''s disease (AD) is initially characterized by synaptic alterations followed by synapse loss and ultimately cell death. Decreased synaptic density that precedes neuronal death is the strongest pathological correlate of cognitive deficits observed in AD. Substantial synapse and neuron loss occur early in disease progression in the entorhinal cortex (EC) and the CA1 region of the hippocampus, when memory deficits become clinically detectable. Mounting evidence suggests that soluble amyloid-ß (Aß) oligomers trigger synapse dysfunction both in vitro and in vivo. However, the neurodegenerative effect of Aß species observed on neuronal culture or organotypic brain slice culture has been more challenging to mimic in animal models. While most of the transgenic mice that overexpress Aß show abundant amyloid plaque pathology and early synaptic alterations, these models have been less successful in recapitulating the spatiotemporal pattern of cell loss observed in AD. Recently we developed a novel animal model that revealed the neurodegenerative effect of soluble low-molecular-weight Aß oligomers in vivo. This new approach may now serve to determine the molecular and cellular mechanisms linking soluble Aß species to neurodegeneration in animals. In light of the low efficiency of AD therapies based on the amyloid cascade hypothesis, a novel framework, the aging factor cascade hypothesis, is proposed in an attempt to integrate the new data and concepts that emerged from recent research to develop disease modifying therapies.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Degeneração Neural , Envelhecimento , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Multimerização Proteica
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