RESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Disfunción Cognitiva , Hipocampo/metabolismo , Condicionamiento Físico Animal/fisiología , Placa Amiloide/metabolismo , Aislamiento Social , Estrés Psicológico , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/metabolismo , Animales , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/prevención & control , Modelos Animales de Enfermedad , Ambiente , Vivienda para Animales , Masculino , Ratones , Ratones Transgénicos , Carrera/fisiología , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Estrés Psicológico/prevención & controlRESUMEN
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 46â¯h after contextual-fear conditioning, and were tested 2-48â¯h later. Interestingly, only mAß infusions within 2â¯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.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Conducta Animal/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Miedo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Inflamación/inducido químicamente , Consolidación de la Memoria/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/administración & dosificación , Animales , Modelos Animales de Enfermedad , Hipocampo/inmunología , Hipocampo/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Infusiones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
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.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastornos del Conocimiento/prevención & control , Agonistas del GABA/uso terapéutico , Hipocampo/metabolismo , Isoxazoles/uso terapéutico , Triazinas/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/patología , Condicionamiento Psicológico/efectos de los fármacos , Miedo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Lipopolisacáridos/toxicidad , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , ARN Mensajero/metabolismoRESUMEN
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.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Trastornos del Conocimiento/metabolismo , Disfunción Cognitiva/metabolismo , Hipocampo/metabolismo , Poli C/farmacología , Proteínas tau/metabolismo , Animales , Cognición/efectos de los fármacos , Cognición/fisiología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/tratamiento farmacológico , Disfunción Cognitiva/diagnóstico , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Fosforilación , Poli C/administración & dosificaciónRESUMEN
For years, the prevailing hypothesis for Alzheimer's Disease (AD) has proposed a mechanism by which deposition of amyloid-beta (Aß) in the brain is independent of tau-pathologies and cognitive decline. However, despite extensive research on the disease, the mechanisms underlying the etiology of tau-pathology remain unknown. Previous research in our lab has shown that imatinib methanesulfonate (IM) blocks the peripheral production of Aß in response to LPS, thereby preventing the buildup of Aß in the hippocampus, and rescuing the cognitive dysfunction that normally follows. The present study aimed to examine the link between Aß and tau following inflammation, and to expand our understanding of how IM affects AD pathology. Specifically, we hypothesized that the IM-mediated inhibition of Aß production following inflammation would successfully protect against the hyperphosphorylation of tau (ptau). Here we show that 7days of LPS treatment in male C57BL/6J mice, which normally produces elevations in peripheral and central Aß, also produces hyperphosphorylation of tau. However, just as pre-treatment and concurrent treatment with IM blocks Aß production, it also blocks the phosphorylation of tau. In addition, 7days of LPS-induced inflammation and Aß production also leads to elevated total tau protein expression. Our results may provide support for the hypothesis that enhanced expression of tau following LPS administration is a protective measure by hippocampal neurons to compensate for the loss of the microtubule-stabilizing protein due to phosphorylation. More importantly, our results support the hypothesis that blocking the production of Aß that follows inflammation also leads to reduced tau phosphorylation, lending credence to a model in which Aß initiates tau phosphorylation.
Asunto(s)
Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Mesilato de Imatinib/farmacología , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Western Blotting , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Peripheral administration of lipopolysaccharide (LPS) elevates production of pro-inflammatory cytokines, and motivates the expression of sickness behaviors. In this study, we tested the ability of an LPS-derived adjuvant, monophosphoryl lipid A (MPLA), to prevent LPS-induced sickness behaviors in a burrowing paradigm. Testing occurred over a three-day period. Animals received a single injection of either MPLA or saline the first two days of testing. On day three, animals received either LPS or saline. Tissue from the dorsal hippocampus was collected for qRT-PCR to assess expression of IL-1ß and IL-4. Results indicate that, during the pre-treatment phase, administration of MPLA induces an immune response sufficient to trigger sickness behaviors. However, we observed that animals pre-treated with MPLA for two days were resistant to LPS-induced sickness behaviors on day three. Results from the qRT-PCR analysis indicated that LPS-treated animals pre-treated with MPLA expressed significantly less IL-1ß compared to LPS-treated animals pre-treated with saline. However, we did not observe a significant difference in IL-4 expression between groups. Therefore, results indicate that under the given parameters of the study, MPLA pre-treatment protects against LPS-induced sickness behaviors, at least in part, by decreasing expression of the pro-inflammatory cytokine IL-1ß.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Conducta de Enfermedad/efectos de los fármacos , Interleucina-1beta/metabolismo , Lípido A/análogos & derivados , Adyuvantes Inmunológicos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Esquema de Medicación , Interleucina-1beta/genética , Interleucina-4/genética , Interleucina-4/metabolismo , Lípido A/administración & dosificación , Lípido A/farmacología , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismoRESUMEN
Recent evidence suggests that inflammation-induced decrements in cognitive function can be mitigated via manipulation of excitatory or inhibitory transmission. We tested the ability of the inverse benzodiazepine agonist, MRK-016 (MRK) to protect against LPS-induced deficits in memory acquisition and consolidation, using a contextual fear conditioning (CFC) paradigm. In Experiment One, mice received lipopolysaccharide (LPS) and/or MRK injections prior to CFC training, and were then tested 24h after training. In Experiment Two, animals received similar treatment injections immediately after training, and were tested 24h later. Additionally, hippocampal samples were collected 4h after LPS injections and immediately after testing, to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA expression. Results indicate that MRK can protect against LPS-induced learning/memory decrements in both paradigms. We also found, in both paradigms, that animals treated with LPS/Saline expressed significantly less BDNF mRNA when compared to Saline/Saline-treated animals 4h after LPS administration, but that MRK did not restore BDNF expression levels. Further, treatment administrations had no effect on IGF-1 mRNA expression at any collection time-point. In summary, MRK-016 can protect against LPS-induced deficits in memory acquisition and consolidation, in this hippocampus-dependent paradigm, though this protection occurs independently of recovery of BDNF expression.
Asunto(s)
Inflamación/tratamiento farmacológico , Isoxazoles/farmacología , Aprendizaje/efectos de los fármacos , Lipopolisacáridos/toxicidad , Memoria/efectos de los fármacos , Nootrópicos/farmacología , Triazinas/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Miedo/efectos de los fármacos , Miedo/fisiología , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inflamación/metabolismo , Inflamación/psicología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Aprendizaje/fisiología , Masculino , Memoria/fisiología , Ratones Endogámicos C57BL , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
B lymphocytes can be divided into different subpopulations, some with distinctive activation requirements and probably mediating specialized functions, based on surface phenotype and/or anatomical location, but the origins of most of these populations remain poorly understood. B cells constrained by transgenesis to produce an Ag receptor derived from a conventional (B-2) type cell develop a B-2 phenotype, whereas cells from mice carrying a B-1-derived receptor acquire the B-1 phenotype. In this study transgenic enforced expression of a B cell receptor (mu/kappa) originally isolated from a CD5+ (B-1a) B cell generates B-1 phenotype cells in bone marrow cultures that show a distinctive B-1 function, survival in culture. Despite their autoreactivity, we find no evidence for receptor editing or that the paucity of B-2 cells is the result of tolerance-induced selection. Finally, Ca2+ mobilization studies reveal a difference between transgenic B-1 cells in spleen and peritoneal cavity, with cells in spleen much more responsive to anti-B cell receptor cross-linking. We discuss these results in terms of specificity vs lineage models for generation of distinctive B cell subpopulations.