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1.
Behav Brain Res ; 378: 112303, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31622640

RESUMO

Although one of the defining characteristics of Alzheimer's disease is the presence of amyloid-beta (Aß) plaques, the early accumulation of soluble Aß oligomers (AßOs) may disrupt synaptic function and trigger cognitive impairments long before the appearance of plaques. Furthermore, murine models aimed at understanding how AßOs alter formation and retrieval of associative memories are conducted using human Aß species, which are more neurotoxic in the mouse brain than the native murine species. Unfortunately, there is currently a lack of attention in the literature as to what the murine version of the peptide (mAß) does to synaptic function and how it impacts the consolidation and retrieval of associative memories. In the current study, adult mice were infused with mAß 0, 2, 6, or 46 h after contextual-fear conditioning, and were tested 2-48 h later. Interestingly, only mAß infusions within 2 h of training reduced freezing behavior at test, indicating that mAß disrupted the consolidation, but not retrieval of fear memory. This consolidation deficit coincided with increased IL-1ß and reduced synaptophysin mRNA levels, without disrupting other synaptic signaling-related genes here examined. Despite differences between murine and human Aß, the deleterious functional outcomes of early-stage synaptic oligomer presence are similar. Thus, models utilizing or inducing the production of mAß in non-transgenic animals are useful in exploring the role of dysregulated synaptic plasticity and resultant learning deficits induced by Aß oligomers.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Inflamação/induzido quimicamente , Consolidação da Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/administração & dosagem , Animais , Modelos Animais de Doenças , Hipocampo/imunologia , Hipocampo/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL
2.
Behav Brain Res ; 379: 112366, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31743728

RESUMO

Research has demonstrated that stress can exacerbate AD pathology in transgenic mouse models of AD. The purpose of the present studies was to extend this work by determining whether a social stressor, isolation stress, would increase the number of Aß plaques in 5xFAD + transgenic mice in comparison to group-housed controls, and accelerate the onset of cognitive deficits in contextual fear-conditioning. Additionally, we aimed to determine whether the pathological impact of isolation stress could be prevented through exposure to exercise alone or to exercise and an enriched environment throughout the isolation period. Two-month-old 5xFAD + and 5xFAD- animals were isolated or group-housed for two and three months. An additional subset of 5xFAD + mice were housed in isolation, housed in isolation with an exercise wheel, or housed in isolation with an exercise wheel and an enriched environment. Both two and three months of isolation stress significantly increased the number of plaques in the hippocampus of 5xFAD + mice, and three months of isolation increased hippocampal BACE1 expression. Isolated animals also displayed a significant cognitive deficit in contextual fear-conditioning, independent of genotype. Furthermore, neither exercise nor an enriched environment were able to prevent these isolation-induced effects. Understanding how stress impacts the onset and progression of AD is critical, as many individuals endure significant stress over their lifespan, including prolonged social isolation, a societal trend likely to worsen with time.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Disfunção Cognitiva , Hipocampo/metabolismo , Condicionamento Físico Animal/fisiologia , Placa Amiloide/metabolismo , Isolamento Social , Estresse Psicológico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Meio Ambiente , Abrigo para Animais , Masculino , Camundongos , Camundongos Transgênicos , Corrida/fisiologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/prevenção & controle
3.
Behav Brain Res ; 359: 871-877, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30031883

RESUMO

Alzheimer's disease is marked by the presence of amyloid-beta (Aß) plaques, elevated central cytokine levels, dysregulation of BDNF-related gene expression, and cognitive decline. Previously, our laboratory has demonstrated that repeated administration of peripheral LPS is sufficient to significantly increase the presence of central Aß in the hippocampus, and that this upregulation corresponds with deficits in learning and memory. We have also previously demonstrated that the inverse benzodiazepine agonist MRK-016 (MRK) can protect against memory acquisition and consolidation errors in mice. To extend these findings, the current study explored the protective effects of MRK in the context of LPS-induced hippocampal Aß accumulation. Hippocampal Aß was significantly elevated, relative to saline-treated animals, following seven days of peripheral LPS injections. Animals were then trained in a contextual fear conditioning paradigm and were immediately treated with MRK or saline once training was complete. Behavioral testing occurred the day after training. Results from this study demonstrate that repeated injections of LPS significantly elevate hippocampal Aß, and inhibit acquisition of contextual fear. Post-training treatment with MRK restored behavioral expression of fear in LPS-treated animals, despite elevated hippocampal Aß, an effect that may be attributed to increased BDNF mRNA expression. Therefore, our data indicate that MRK can prevent LPS- induced cognitive deficits associated with elevated Aß, and restore hippocampal BDNF expression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/prevenção & controle , Agonistas GABAérgicos/uso terapêutico , Hipocampo/metabolismo , Isoxazóis/uso terapêutico , Triazinas/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/patologia , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , RNA Mensageiro/metabolismo
4.
Behav Brain Res ; 313: 219-225, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27449203

RESUMO

Alzheimer's disease is marked by the accumulation of the amyloid-beta (Aß) peptide, and increases in phosphorylation of the microtubule associated protein, tau. Changes in these proteins are considered responsible, in part, for the progressive neuronal degeneration and cognitive deficits seen in AD. We examined the effect of repeated consecutive peripheral poly I:C injections on cognitive deficits, central Aß, and phosphorylated tau accumulation, following three treatment durations: 7, 14, and 21 days. Forty-eight hours after the final injection, animals were trained in a contextual fear-conditioning paradigm, and tested 24h later. Immediately after testing, the hippocampus was collected to quantify Aß and phosphorylated tau accumulation. Results showed that, although poly I:C-induced Aß was significantly elevated at all time points examined, poly I:C only disrupted cognition after 14 and 21 days of administration. Moreover, elevations in phosphorylated tau were not seen until the 14-day time point. Interestingly, phosphorylated tau expression then declined at the 21-day time point. Finally, we demonstrated that Aß levels are a stronger predictor of cognitive dysfunction, explaining 37% of the variance, whereas phosphorylated tau levels only accounted for 0.2%. Taken together, these results support the hypothesis that inflammation-induced elevation in Aß disrupts cognition, independently of phosphorylated tau, and suggest that long-term administration of poly I:C may provide a model to investigate the contribution of long-term inflammation toward the development of Alzheimer's-like pathology.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Poli C/farmacologia , Proteínas tau/metabolismo , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/tratamento farmacológico , Disfunção Cognitiva/diagnóstico , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Poli C/administração & dosagem
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