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The frequent intake of ultra-processed, heat-processed, and fat-enriched foods rich in dietary advanced lipoxidation end-products (ALEs) has been correlated with cognitive decline; however, the underlying mechanisms of action remain unexplored. This study investigated the impact of a 12-month dietary exposure to ALEs on learning, memory, and Aß1-42 accumulation in mice, with a focus on the AMPK/SIRT1 signaling pathway and ADAM10 expression. The gut microbiota and metabolomic profiles revealed ALEs-induced gut dysbiosis and cognitive impairment, highlighting modulation through the microbiota-gut-brain axis. Key findings include increased pathogenic bacteria and decreased beneficial bacteria, linked to metabolite profile changes that affect neurotoxic Aß1-42 peptide accumulation. This long-term comprehensive study underscores the need for dietary guidelines to reduce ALE intake and mitigate neurodegenerative disease risk, highlighting the intricate interplay between diet, gut microbiota, and cognitive health.
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Eje Cerebro-Intestino , Encéfalo , Cognición , Disfunción Cognitiva , Microbioma Gastrointestinal , Peroxidación de Lípido , Ratones Endogámicos C57BL , Animales , Ratones , Masculino , Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Humanos , Cognición/efectos de los fármacos , Bacterias/metabolismo , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , Péptidos beta-Amiloides/metabolismo , Disbiosis/metabolismo , Disbiosis/microbiologíaRESUMEN
Alzheimer's disease (AD) is the leading cause of dementia worldwide with therapeutic lacunae till date. The beta-amyloid (Aß) accumulation triggers AD pathogenesis, though clinical trials lowering Aß have not altered disease outcomes suggesting other interacting factors to be identified for drug design of AD. Therefore, it is of interest to identify potential hub proteins interlinked with disease-driving pathways using a network-based approach for AD therapeutic designing. Literature mining was done to identify proteins implicated in AD etiology. Protein-protein interactions (PPIs) were retrieved from the STRING database and merged into a single network using Cytoscape 3.10.1. The hub proteins involved in AD etiology were predicted based on the topological algorithms of CytoHubba. Six major proteins, with STRING database identifiers - APP, BACE1, PSEN1, MAPT, APOE4 and TREM2, were identified to be involved in AD pathogenesis. The merged network of PPIs of these proteins contained 51 nodes and 211 edges, as predicted by Analyzer module of Cytoscape. The Amyloid precursor protein (APP) emerged as the highest-scoring hub protein across multiple centrality measures and topological algorithms. Thus, current data provides evidence to support the ongoing investigation of APP's multifaceted functions and therapeutic potential for AD.
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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent risk factor for cognitive impairment. Cerebral amyloid-ß (Aß) accumulation, as an important pathology of cognitive impairment, can be caused by impaired Aß clearance in the periphery. The liver is the primary organ for peripheral Aß clearance, but the role of peripheral Aß clearance in NAFLD-induced cognitive impairment remains unclear. METHODS: We examined correlations between NAFLD severity, Aß accumulation, and cognitive performance in female Sprague-Dawley rats. The impact of NAFLD on hepatic Aß clearance and the involvement of low-density lipoprotein receptor-related protein 1 (LRP-1) were assessed in rat livers and cultured hepatocytes. Additionally, a case-control study, including 549 NAFLD cases and 549 controls (782 males, 316 females), investigated the interaction between NAFLD and LRP-1 rs1799986 polymorphism on plasma Aß levels. FINDINGS: The severity of hepatic steatosis and dysfunction closely correlated with plasma and cerebral Aß accumulations and cognitive deficits in rats. The rats with NAFLD manifested diminished levels of LRP-1 and Aß in liver tissue, with these reductions inversely proportional to plasma and cerebral Aß concentrations and cognitive performance. In vitro, exposure of HepG2 cells to palmitic acid inhibited LRP-1 expression and Aß uptake, which was subsequently reversed by a peroxisome proliferator-activated receptor α (PPARα) agonist. The case-control study revealed NAFLD to be associated with an increment of 8.24% and 10.51% in plasma Aß40 and Aß42 levels, respectively (both P < 0.0001). Moreover, the positive associations between NAFLD and plasma Aß40 and Aß42 levels were modified by the LRP-1 rs1799986 polymorphism (P for interaction = 0.0017 and 0.0015, respectively). INTERPRETATION: LRP-1 mediates the adverse effect of NAFLD on peripheral Aß clearance, thereby contributing to cerebral Aß accumulation and cognitive impairment in NAFLD. FUNDING: Major International (Regional) Joint Research Project, National Key Research and Development Program of China, National Natural Science Foundation of China, and the Angel Nutrition Research Fund.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad del Hígado Graso no Alcohólico , Masculino , Ratas , Femenino , Animales , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estudios de Casos y Controles , Ratas Sprague-Dawley , Péptidos beta-Amiloides/metabolismo , Hígado/metabolismo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Enfermedad de Alzheimer/metabolismoRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disease that mainly affects older adults. Although the global burden of AD is increasing year by year, the causes of AD remain largely unknown. Numerous basic and clinical studies have shown that interleukin-17A (IL-17A) may play a significant role in the pathogenesis of AD. A comprehensive assessment of the role of IL-17A in AD would benefit the diagnosis, understanding of etiology and treatment. However, over the past decade, controversies remain regarding the expression level and role of IL-17A in AD. We have incorporated newly published researches and point out that IL-17A expression levels may vary along with the development of AD, exercising different roles at different stages of AD, although much more work remains to be done to support the potential role of IL-17A in AD-related pathology. Here, it is our intention to review the underlying mechanisms of IL-17A in AD and address the current controversies in an effort to clarify the results of existing research and suggest future studies.
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Enfermedad de Alzheimer , Interleucina-17 , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Interleucina-17/inmunología , Interleucina-17/fisiologíaRESUMEN
Intracellular Aß (iAß) expression, extracellular Aß (eAß) plaque formation and microglial reactivity are characteristic neuropathological events of Alzheimer's disease (AD) and have been detected in several transgenic mouse models of this disease. In this work we decided to investigate the early (2-7 months of age) development of these phenomena at both regional and cellular levels in 5XFAD mice, a severe transgenic mouse model of AD. We demonstrated that 1) Aß pathology develops in many but not all brain regions, 2) iAß is transient and almost always followed by eAß in grey matter regions, and the respective levels are roughly proportional, and 3) in about 1/3 of the grey matter regions with Aß pathology and in several white matter regions, eAß plaques can appear where no iAß-positive structures were detected. We also showed that male and female mice share a similar regional and cellular pattern of Aß pathology development that is more prominent in females. Early iAß is associated to the activation of microglia, while subsequent formation of eAß plaques is associated with markedly increased density of microglial cells that acquire a characteristic clustered phenotype. Present analysis is relevant to set a reference for pathophysiological studies and to define specific targets for the test of therapeutic interventions in this widely used AD transgenic model.
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Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Corteza Cerebral/patología , Placa Amiloide/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Péptidos beta-Amiloides/análisis , Animales , Corteza Cerebral/citología , Corteza Cerebral/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Microglía/inmunología , Microglía/metabolismo , Microglía/patología , Placa Amiloide/genética , Placa Amiloide/inmunología , Factores SexualesRESUMEN
We have previously identified antimony (Sb) as a newly nerve poison which leads to neuronal apoptosis. However, the relationship between Sb exposure and Alzheimer's disease (AD) process lacks direct evidence. HE staining and Nissl staining showed significant nerve damage after Sb exposure. Therefore, we further evaluated Sb-associated AD risk by detecting accumulation of ß-amyloid protein (Aß) and neurofibrillary tangles (NFTs) in the brains of mice exposed to Sb for 4 and 8 weeks, and even 1 year. The results showed that dose of 20 mg/kg induced Aß accumulation, but not tau hyperphosphorylation after exposure for 4 week. Eight weeks later, both 10 and 20 mg/kg dramatically triggered Aß accumulation and increased tau phosphorylation at ser199. At the same time, 20 mg/kg could also increase tau phosphorylation at ser396 and number of NFTs. One years later, we found all of AD hallmarks detected in present study showed positive results in the brains of mice exposed to Sb at 10 and 20 mg/kg. In summary, our data provided direct evidence of Sb-associated AD risk, drawing more attention to Sb-triggered neurotoxicity.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/inducido químicamente , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Antimonio/toxicidad , Encéfalo/metabolismo , Ratones , Ratones Transgénicos , Fosforilación , Proteínas tau/metabolismoRESUMEN
Accumulation of aggregated amyloid beta (Aß) in the brain is believed to impair multiple cellular pathways and play a central role in Alzheimer's disease pathology. However, how this process is regulated remains unclear. In theory, measuring protein synthesis is the most direct way to evaluate a cell's response to stimuli, but to date, there have been few reliable methods to do this. To identify the protein regulatory network during the development of Aß deposition in AD, we applied a new proteomic technique to quantitate newly synthesized protein (NSP) changes in the cerebral cortex and hippocampus of 2-, 5-, and 9-month-old APP/PS1 AD transgenic mice. This bio-orthogonal noncanonical amino acid tagging analysis combined PALM (pulse azidohomoalanine labeling in mammals) and HILAQ (heavy isotope labeled AHA quantitation) to reveal a comprehensive dataset of NSPs prior to and post Aß deposition, including the identification of proteins not previously associated with AD, and demonstrated that the pattern of differentially expressed NSPs is age-dependent. We also found dysregulated vesicle transportation networks including endosomal subunits, coat protein complex I (COPI), and mitochondrial respiratory chain throughout all time points and two brain regions. These results point to a pathological dysregulation of vesicle transportation which occurs prior to Aß accumulation and the onset of AD symptoms, which may progressively impact the entire protein network and thereby drive neurodegeneration. This study illustrates key pathway regulation responses to the development of AD pathogenesis by directly measuring the changes in protein synthesis and provides unique insights into the mechanisms that underlie AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , ProteómicaRESUMEN
INTRODUCTION: Previous studies have shown contrasting results in determining efficacy of statins against amyloid beta accumulation. The aim of this study was to assess the impact of statin in AD. METHOD: We searched PubMed and Embase for relevant preclinical studies. A meta-analysis of the statin's efficacy on amyloidosis and cognitive impairment was performed. Also, stratified analysis was performed on several covariates including the type of statin used, gender and age of rodents and duration of statin therapy, to account for the reported heterogeneity in the results obtained. The study protocol was registered in PROSPERO (CRD42018102557). RESULT: 17 studies including 22 comparisons, containing a sample size of 446 rodents, participated in the meta-analysis of statin's effect on overall Aß deposition. Although the effect of statin on overall Aß deposition was found to be protective (p < 0.00001) but as we categorized the efficacy of statin on different Aß species (soluble and insoluble Aß40/42) and Aß plaque load, we found that significance in the protection decreased. A stratified meta-analysis demonstrated a significant role in the duration of statin supplements and rodent's age on the heterogeneity of the results. Statin administered to rodents for the longest duration (>6 months) and younger rodents (<6 months of age) demonstrated significant efficacy of statin on Aß deposition. CONCLUSION: Statin showed reduction in Aß level but stratified analysis revealed that this effect of statin was dependent on rodent's age and duration of the treatment.
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Amiloidosis/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Amiloidosis/metabolismo , Animales , Modelos Animales de Enfermedad , RoedoresRESUMEN
OBJECTIVE: It is reported that miR-26a-5p could regulate neuronal development, but its underlying mechanisms in Alzheimer's disease (AD) progression is unclear. METHODS: APP (swe)/PS1 (ΔE9) transgenic mice served as AD mice. Morris water maze test was used to measure the spatial learning and memory ability of mice. The expressions of miR-26a-5p, DYRK1A, phosphorylated-Tau, Aß40, and Aß42 were detected. The relationship between miR- 26a-5p and DYRK1A was explored using dual luciferase reporter assay. The effects of miR-26a- 5p on AD mice was determined. RESULTS: AD mice walked a lot of wrong ways to find the platform area and the latency time to reach the platform was longer. There was low expression of MiR-26a-5p in AD mice. Overexpression of miR-26a-5p inhibited Tau phosphorylation and Aß accumulation. MiR-26a-5p negatively regulated DYRK1A via targeting its 3'UTR. In vivo, increased miR-26a-5p down-regulated Aß40, Aß42, p-APP and p-Tau levels in AD mice through decreasing DYRK1A. Meanwhile, the swimming path and the latency time, to reach the platform, was shorten after enhancing miR-26a-5p expression. CONCLUSION: Overexpression of miR-26a-5p could repress Tau phosphorylation and Aß accumulation via down-regulating DYRK1A level in AD mice.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , MicroARNs/biosíntesis , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Tirosina Quinasas/biosíntesis , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/genética , Animales , Línea Celular Tumoral , Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/genética , Fosforilación/fisiología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Proteínas tau/antagonistas & inhibidores , Proteínas tau/genética , Quinasas DyrKRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative disorder. The pathogenesis of AD is very complicated. For decades, the amyloid hypothesis has influenced and guided research in the field of AD. Meanwhile, researchers gradually realized that AD is caused by multiple concomitant factors, such as autophagy, mitochondrial quality control, insulin resistance and oxidative stress. In current clinical trials, the improvement strategies of AD, such as Aß antibody immunotherapy and gamma secretase inhibitors, are limited. There is mounting evidence of neurodegenerative disorders indicated that activation of AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. We reviewed the researches on AMPK for AD, the results demonstrated that activation of AMPK is controversial in Aß deposition and tau phosphorylation, but is positive to promote autophagy, maintain mitochondrial quality control, reduce insulin resistance and relieve oxidative stress. It is concluded that AMPK might be a new target for AD by aggressively treating the risk factors in the future.
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Proteínas Quinasas Activadas por AMP/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Aminoimidazol Carboxamida/análogos & derivados , Péptidos beta-Amiloides/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Pironas/uso terapéutico , Ribonucleótidos/uso terapéutico , Tiofenos/uso terapéutico , Proteínas tau/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Aminoimidazol Carboxamida/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/genética , Autofagia/efectos de los fármacos , Autofagia/genética , Compuestos de Bifenilo , Ensayos Clínicos como Asunto , Regulación de la Expresión Génica , Humanos , Resistencia a la Insulina , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Crocetin, an agent derived from saffron, has multiple pharmacological properties, such as neuroprotective, anti-oxidant, and anti-inflammatory actions. These properties might benefit the treatment of Alzheimer's disease (AD). In the present study, we tested whether crocetin attenuates inflammation and amyloid-ß (Aß) accumulation in APPsw transgenic mice, AD mouse models. Cell viability and the levels of Aß40 and Aß42 in HeLa cells stably transfected with Swedish mutant APP751 were evaluated. Mice with Swedish mutant APP751 transgene were used as transgenic mouse models of AD, and were orally administrated with crocetin. Aß protein and inflammatory cytokines were measured with ELISA. NF-κB and P53 were measured with western blot assay. Learning and memory were analyzed with Morris water maze and novel object recognition tests. RESULTS: Crocetin significantly reduced Aß40 and Aß42 secretion in Hela cells without effecting cell viability. In AD transgenic mice, crocetin significantly reduced the pro-inflammatory cytokines and enhanced anti-inflammatory cytokine in plasma, suppressed NF-κB activation and P53 expression in the hippocampus, decreased Aß in various brain areas, and improved learning and memory deficits. CONCLUSION: Crocetin improves Aß accumulation-induced learning and memory deficit in AD transgenic mice, probably due to its anti-inflammatory and anti-apoptotic functions.
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BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disease, is associated with dysfunction of the olfactory and the entorhinal cortex of the brain that control memory and cognitive functions and other daily activities. Pro-inflammatory cytokines, amyloid-ß (Aß), and the cholinergic system play vital roles in the pathophysiology of AD. However, the role of changes in cholinergic system components, Aß accumulation, and cytokines in both the olfactory and entorhinal cortex is not known clearly. OBJECTIVE: The present study is aimed to evaluate the changes of cholinergic system components, Aß accumulation, and cytokines in both the olfactory bulb (OB) and entorhinal cortex (EC) of young and aged APPSWE/PS1dE9 transgenic (Tg) mice. METHODS: We have explored the changes of cholinergic system components, Aß accumulation, and expression profiling of cytokines in the OB and EC of aged APPswe transgenic mice and age-matched wild type mice using quantitative Real-Time PCR assays and immunohistochemistry techniques. RESULTS: In aged Tg mice, a significant increase of expression of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and chemokine MCP1 (pâ<â0.001, pâ<â0.001, and pâ=â0.001, respectively) and a significant reduction of nAChRα4 (pâ=â0.048) and AChE (pâ=â0.023) was observed when compared with age-matched wild type mice. Higher levels of AChE and BuChE are expressed in OB and EC of the APPSWE/PS1dE9 of Tg mice. Aß accumulation was observed in OB and EC of the APPSWE/PS1dE9 of Tg mice. CONCLUSION: The study demonstrates the expression profiling of pro-inflammatory cytokines and cholinergic markers as well as Aß accumulation in OB and EC of the APPSWE/PS1dE9 Tg mice. Moreover, the study also demonstrated that the APPSWE/PS1dE9 Tg mice can be useful as a mouse model to understand the role of pro-inflammatory cytokines and cholinergic markers in pathophysiology of AD.
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Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Citocinas/metabolismo , Corteza Entorrinal/metabolismo , Bulbo Olfatorio/metabolismo , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/patología , Animales , Butirilcolinesterasa/metabolismo , Modelos Animales de Enfermedad , Corteza Entorrinal/patología , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Ratones Transgénicos , Bulbo Olfatorio/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Nicotínicos/metabolismoRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-ß peptide (Aß) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AßPP/Aß in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative stress in an early stage of pathology in a transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Espectroscopía de Resonancia por Spin del Electrón , Mitocondrias/metabolismo , Estrés Oxidativo/fisiología , Adenosina Trifosfato/metabolismo , Edad de Inicio , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Cognición/fisiología , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Humanos , Masculino , Aprendizaje por Laberinto/fisiología , Ratones Transgénicos , Especies Reactivas de Oxígeno/metabolismo , Memoria Espacial/fisiologíaRESUMEN
The progressive aggregation of amyloid-ß protein (Aß) into senile plaques is a major pathological factor of Alzheimer's disease (AD) and is believed to result in memory impairment. We aimed to investigate the effect of an optimized combination of ginger and peony root (OCGP), a standardized herbal mixture of ginger and peony root, on Aß accumulation and memory impairment in amyloid-ß protein precursor (AßPP)/presenilin 1 (PS1) double-transgenic mice. In an in vitro thioflavin T fluorescence assay, 100 µg/ml OCGP inhibited Aß accumulation to the same extent as did 10 µM curcumin. Furthermore, AßPP/PS1 double-transgenic mice treated with OCGP (50 or 100âmg/kg/day given orally for 14 weeks) exhibited reduced Aß plaque accumulation in the hippocampus and lower levels of glial fibrillary acid protein and cyclooxygease-2 expression compared with vehicle-treated controls. These results suggest that OCGP may prevent memory impairment in AD by inhibiting Aß accumulation and inflammation in the brain.
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Paeonia , Fitoterapia/métodos , Placa Amiloide/patología , Zingiber officinale , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Análisis de Varianza , Animales , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Zingiber officinale/química , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Masculino , Ratones , Ratones Transgénicos , Mutación/genética , Paeonia/química , Preparaciones de Plantas/uso terapéutico , Placa Amiloide/tratamiento farmacológico , Presenilina-1/genéticaRESUMEN
Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has previously been implicated in Alzheimer's disease (AD)-related cognitive impairment. We aimed to determine the relationship between BDNF Val66Met and beta-amyloid (Aß) on cognitive decline, hippocampal atrophy, and Aß accumulation over 36 months in 165 healthy adults enrolled in the Australian Imaging, Biomarkers and Lifestyle study. In healthy adults with high Aß, Met carriers showed significant and moderate-to-large declines in episodic memory, executive function, and language, and greater hippocampal atrophy over 36 months, compared with Val/Val homozygotes. BDNF Val66Met was not found to be related to rates of change in cognition or hippocampal volume in healthy adults with low Aß. BDNF Val66Met did not relate to the amount of Aß or to the rate of Aß accumulation in either group. High Aß levels coupled with Met carriage may be useful prognostic markers of accelerated cognitive decline and hippocampal degeneration in individuals in the preclinical stage of AD.