RESUMEN
Most patients with Alzheimer's disease (AD) develop neuropsychiatric symptoms (NPS) alongside cognitive decline, and apathy is one of the most common symptoms. Few preclinical studies have investigated the biological substrates underlying NPS in AD. In this study, we used a cross-sectional design to characterize apathy-like behaviors and assess memory in 5xFAD and wildtype control mice at 6, 12, and 16 months of age. Nest building, burrowing, and marble burying were used to test representative behaviors of apathy, and a composite score of apathy-like behavior was generated from these assays. Soluble Aß42 and plaques were quantified in the prefrontal cortex and hippocampus of the 5xFAD mice with the highest and lowest composite scores using ELISA and histology. Results suggest that 5xFAD mice develop significant apathy-like behaviors starting at 6 months of age that worsen with aging and are positively correlated with soluble Aß42 and plaques in the prefrontal cortex and hippocampus. Our findings highlight the utility of studying NPS in mouse models of AD to uncover important relationships with underlying neuropathology.
Asunto(s)
Enfermedad de Alzheimer , Apatía , Ratones , Animales , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Estudios Transversales , Ratones Transgénicos , Modelos Animales de EnfermedadRESUMEN
Transgenic mouse models of Aß amyloidosis generated by knock-in of a humanized Aß sequence can offer some advantages over the transgenic models that overexpress amyloid precursor protein (APP). However, systematic comparison of memory, behavioral, and neuropathological phenotypes between these models has not been well documented. In this study, we compared memory and affective behavior in APPNLGF mice, an APP knock-in model, to two widely used mouse models of Alzheimer's disease, 5xFAD and APP/PS1 mice, at 10 months of age. We found that, despite similar deficits in working memory, object recognition, and social recognition memory, APPNLGF and 5xFAD mice but not APP/PS1 mice show compelling anxiety- and depressive-like behavior, and exhibited a marked impairment of social interaction. We quantified corticolimbic Aß plaques, which were lowest in APPNLGF, intermediate in APP/PS1, and highest in 5xFAD mice. Interestingly, analysis of plaque size revealed that plaques were largest in APP/PS1 mice, intermediate in 5xFAD mice, and smallest in APPNLGF mice. Finally, we observed a significantly higher percentage of the area occupied by plaques in both 5xFAD and APP/PS1 relative to APPNLGF mice. Overall, our findings suggest that the severity of Aß neuropathology is not directly correlated with memory and affective behavior impairments between these three transgenic mouse models. Additionally, APPNLGF may represent a valid mouse model for studying AD comorbid with anxiety and depression.
Asunto(s)
Afecto , Precursor de Proteína beta-Amiloide/genética , Encéfalo/patología , Memoria , Oligopéptidos/genética , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/fisiología , Animales , Femenino , Locomoción , Masculino , Memoria a Corto Plazo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Prueba del Laberinto Acuático de Morris , Oligopéptidos/metabolismo , Oligopéptidos/fisiología , Prueba de Campo Abierto , Interacción SocialRESUMEN
INTRODUCTION: Exposure to stress, mediated through the hypothalamic-pituitary-adrenal (HPA) axis, elicits sex differences in endocrine, neurological, and behavioral responses. However, the sex-specific factors that confer resilience or vulnerability to stress and stress-associated psychiatric disorders remain largely unknown. The evident sex differences in stress-related disease prevalence suggest the underlying differences in the neurobiological underpinnings of HPA axis regulation. METHOD: Here, we used a chronic unpredictable stress (CUS) model to investigate the behavioral and biochemical responses of the HPA axis in C57BL/6 mice. Animals were tested in the open field and forced swim test to examine anxiety-like and depressive-like behaviors. Plasma corticosterone levels were measured after behavior and CUS, and glucocorticoid receptor (GR) expression and cytosolic and nuclear fractions of binding protein FKBP51 expression were taken to measure function and regulation of the stress response. RESULTS: Our results indicate increased depressive-like behavior in males and females which correlated with increased corticosterone levels following CUS. However, females displayed more anxiety-like behaviors with and without CUS. Interestingly, we found trends toward dysregulation of GR protein expression in CUS females, and an increase in the GR inhibitory protein, FKBP51, in the cytosol of CUS males but not females. CONCLUSION: These results suggest biochemical alterations to the HPA axis regulation which may elicit a glucocorticoid resistance in females after chronic stress and may contribute to the sex-biased vulnerability to stress-related psychiatric disorders.
Asunto(s)
Conducta Animal/fisiología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/metabolismo , Animales , Ansiedad/metabolismo , Corticosterona/sangre , Depresión/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Factores Sexuales , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
Approximately two-thirds of those suffering with Alzheimer's disease (AD) are women, however, the biological mechanisms underlying this sex divergence of AD prevalence remain unknown. Previous research has shown sex-specific biochemical differences that bias female mice toward pro-AD signaling on the phosphoproteomic level via corticotropin releasing factor (CRF) receptor 1 activation after CRF overexpression. Here we aimed to determine if chronic stress would induce a similar response in AD mouse models. We stressed 4-month-old APP/PS1 mice using a chronic unpredictable mild stress (CUMS) paradigm for up to 1 month. Following CUMS and behavioral assessments, we quantified whole protein and phosphoprotein levels in the cortex of stressed and non-stressed APP/PS1 mice using mass spectrometry-based proteomics. While there were no statistically significant differences at the total protein and peptide abundance levels, we found 909 and 841 statistically significant phosphopeptides between stressed and unstressed females and males, respectively, using a false discovery rate of 5%. Of these significant phosphopeptides, only 301 were the same in males and females. These results indicate that while both males and females undergo protein phosphorylation changes following stress, the peptides that are phosphorylated differ between sexes. We then used Metacore analysis to determine which biological pathways were affected. We found that several pathways were changed differently between male and female mice including NMDA receptor trafficking, cytoskeleton organization, and tau pathology. The differing biological pathways affected between males and females in response to chronic stress may help us to better understand why women are at a higher risk of AD.
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Encéfalo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fosfoproteínas/metabolismo , Estrés Psicológico/complicaciones , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Cromatografía de Afinidad , Modelos Animales de Enfermedad , Femenino , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Prueba del Laberinto Acuático de Morris , Fosforilación , Presenilina-1/metabolismo , Proteómica/métodos , Factores Sexuales , Estrés Psicológico/metabolismoRESUMEN
Glioma is a primary, malignant, and aggressive brain tumor in adults. To develop new therapeutic strategies for glioma, we must determine its underlying mechanisms. In the present study, we aimed to investigate the potential role of miR-1272-ADAM9-CDCP1 signaling in the progression of glioma. We found that ectopic expression of miR-1272 produced significant inhibitory effects on cell proliferation and migration and was associated with cell cycle G0/G1 arrest in A172 and SHG44 glioma cells. Using the luciferase reporter assay, we identified ADAM9 as a target of miR-1272. The expression of ADAM9 was markedly decreased or increased after overexpression or inhibition, respectively, of miR-1272 in glioma cells. Moreover, overexpression of ADAM9 reversed the inhibitory effects of miR-1272 on glioma cell progression. Furthermore, CDCP1 served as a potential downstream molecule of miR-1272/ADAM9 signaling in glioma and promoted the proliferation and migration of glioma. Results derived from clinical samples and online databases confirmed correlations between the expression of ADAM9 and CDCP1 and both the severity and prognosis of glioma. In conclusion, these results suggest that miR-1272 and CDCP1 may act as novel regulators in glioma. The miR-1272/ADAM9/CDCP1 pathway may serve as a potential candidate pathway for the prevention of glioma.
Asunto(s)
Proteínas ADAM/genética , Antígenos de Neoplasias/genética , Neoplasias Encefálicas/genética , Moléculas de Adhesión Celular/genética , Glioma/genética , Proteínas de la Membrana/genética , MicroARNs/metabolismo , Proteínas ADAM/metabolismo , Antígenos de Neoplasias/metabolismo , Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Moléculas de Adhesión Celular/metabolismo , Línea Celular , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Glioma/metabolismo , Glioma/patología , Humanos , Proteínas de la Membrana/metabolismo , MicroARNs/genética , Transducción de SeñalRESUMEN
Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women in both disease prevalence and severity, but the mechanisms underlying this sex divergence are unknown. Though some have suggested this difference in risk is a reflection of known differences in longevity between men and women, mounting clinical and preclinical evidence supports women also having intrinsic susceptibilities towards the disease. While a number of potential risk factors have been hypothesized to affect these differences in risks, none have been definitively verified. In this review, we discuss a novel hypothesis whereby women's susceptibility to chronic stress also mediates increased risk for AD. As stress is a risk factor for AD, and women are twice as likely to develop mood disorders where stress is a major etiology, it is possible that sex dimorphisms in stress responses contribute to the increase in women with AD. In line with this, sex divergence in biochemical responses to stress have been noted along the hypothalamic-pituitary-adrenal (HPA) axis and among known molecular effectors of AD, with crosstalk between these processes also being likely. In addition, activation of the cortical corticotrophin-releasing factor receptor 1 (CRF1) signaling pathway leads to distinct female-biased increases in molecules associated with AD pathogenesis. Therefore, the different biochemical responses to stress between women and men may represent an intrinsic, sex-dependent risk factor for AD.
RESUMEN
Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer's disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.