RESUMEN
Objective: The objective of the study is to investigate whether quercetin ameliorates Alzheimer's disease (AD)-like pathology in APP/PS1 double transgenic mice and its hypothesized mechanism, contributing to the comprehension of AD pathogenesis. Methods: A total of 30 APP/PS1 transgenic mice were randomized into model group (APP/PS1), quercetin group (APP/PS1+Q), and donepezil hydrochloride group (APP/PS1+DON). Simultaneously, there were 10 C57 mice of the same age served as a control group. Three months posttreatment, the effects of quercetin on AD mice were evaluated using the Morris water maze (MWM) test, Y maze experiment, immunohistochemistry, immunofluorescence, and western blotting. Results: Results from the water maze and Y maze indicated that quercetin significantly improved cognitive impairment in APP/PS1 transgenic AD mice. Additionally, serum enzyme-linked immunosorbent assay (ELISA) results demonstrated that quercetin elevated MDA, superoxide dismutase (SOD), CAT, GSH, acetylcholine (ACh), and acetylcholinesterase (AChE) levels in AD mice. Hematoxylin-eosin (HE) staining, Nissl staining, and hippocampal tissue thioflavine staining revealed that quercetin reduced neuronal damage and Aß protein accumulation in AD mice. Western blot validated protein expression in the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathway associated with oxidative stress and apoptosis, confirming quercetin's potential molecular mechanism of enhancing AD mouse cognition. Furthermore, western blot findings indicate that quercetin significantly alters protein expression in the Keap1/Nrf2/HO-1 pathway. Moreover, molecular docking analysis suggests that Keap1, NQO1, HO-1, caspase-3, Bcl-2, and Bax proteins in the Keap1/Nrf2/HO-1 pathway may be potential regulatory targets of quercetin. These findings will provide a molecular basis for quercetin's clinical application in AD treatment. Conclusion: Quercetin can improve cognitive impairment and AD-like pathology in APP/PS1 double transgenic mice, potentially related to quercetin's activation of the Keap1/Nrf2/HO-1 pathway and reduction of cell apoptosis.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Apoptosis , Encéfalo , Disfunción Cognitiva , Modelos Animales de Enfermedad , Hemo-Oxigenasa 1 , Proteína 1 Asociada A ECH Tipo Kelch , Ratones Transgénicos , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Quercetina , Animales , Quercetina/farmacología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Ratones , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Hemo-Oxigenasa 1/metabolismo , Apoptosis/efectos de los fármacos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Transducción de Señal/efectos de los fármacos , Presenilina-1/genética , Presenilina-1/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Antioxidantes/farmacología , Antioxidantes/metabolismoRESUMEN
Alzheimer's disease (AD), characterized by cognitive decline, is increasingly recognized as a disorder marked by synaptic loss and dysfunction. Despite this understanding, the underlying pathophysiological mechanisms contributing to synaptic impairment remain largely unknown. In this study, we elucidate a previously undiscovered signaling pathway wherein the S-nitrosylation of the Cdk5 activator p39, a post-translational modification involving the addition of nitric oxide to protein cysteine residues, plays a crucial role in synaptic dysfunction associated with AD. Our investigation reveals heightened p39 S-nitrosylation in the brain of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. Additionally, soluble amyloid-ß oligomers (Aß), implicated in synaptic loss in AD, induce p39 S-nitrosylation in cultured neurons. Notably, we uncover that p39 protein level is regulated by S-nitrosylation, with nitric oxide S-nitrosylating p39 at Cys265 and subsequently promoting its degradation. Furthermore, our study demonstrates that S-nitrosylation of p39 at Cys265 significantly contributes to amyloid-ß (Aß) peptide-induced dendrite retraction and spine loss. Collectively, our findings highlight S-nitrosylation of p39 as a novel aberrant redox protein modification involved in the pathogenesis of AD, suggesting its potential as a therapeutic target for the disease.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones Transgénicos , Animales , Péptidos beta-Amiloides/metabolismo , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Sinapsis/metabolismo , Óxido Nítrico/metabolismo , Procesamiento Proteico-Postraduccional , Proteolisis , Neuronas/metabolismo , Modelos Animales de Enfermedad , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Humanos , Presenilina-1/metabolismo , Presenilina-1/genética , Ratones Endogámicos C57BL , FosfotransferasasRESUMEN
Alzheimer's disease (AD) is characterized by progressive cognitive decline and late-stage neurobehavioral issues marked by amyloid-beta plaques and Tau protein tangles. This study aims to investigate Fibulin-1(FBLN1) gene expression in the hippocampal tissue of Presenilin-1/Presenilin-2 conditional double-knockout (DKO) and double-transgenic (DTG) mice, using single-cell sequencing and experimental methods to verify abnormal methylation status and correlation with AD. Genomic DNA from DKO and DTG mice was used for genotyping. Reduced Representation Bisulfite Sequencing (RRBS) identified 10 genes with abnormal methylation changes, with protein-protein interaction (PPI) analysis highlighting five core genes, including FBLN1. Single-cell sequencing, RT-PCR, and Western blotting (WB) were used to analyze FBLN1 mRNA and protein levels in the hippocampal tissues of early-stage and mid-stage AD DKO, DTG, and CBAC57 mice. RRBS identified 10 genes with abnormal methylation, with PPI highlighting five core genes. Single-cell sequencing showed significant FBLN1 expression in AD groups. RT-PCR and WB indicated elevated FBLN1 mRNA and protein levels in mid-stage AD DKO and DTG mice compared to CBAC57 mice, with no differences in early-stage AD DKO and CBAC57 mice. RRBS revealed hypomethylation of the FBLN1 gene in mid-stage AD DKO mice. Elevated FBLN1 expression in AD models suggests an age-dependent neurodegenerative mechanism independent of amyloid-beta deposition. This study enhances our understanding of AD's epigenetic mechanisms, which will aid targeted diagnosis, treatment, and prognosis.
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Enfermedad de Alzheimer , Biología Computacional , Metilación de ADN , Modelos Animales de Enfermedad , Hipocampo , Ratones Noqueados , Presenilina-2 , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Hipocampo/metabolismo , Hipocampo/patología , Ratones , Biología Computacional/métodos , Presenilina-2/genética , Presenilina-2/metabolismo , Ratones Transgénicos , Presenilina-1/genética , Presenilina-1/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Masculino , Epigénesis GenéticaRESUMEN
Mutations in the PSEN genes are the major cause of familial Alzheimer's disease, and presenilin (PS) is the catalytic subunit of γ-secretase, which cleaves type I transmembrane proteins, including the amyloid precursor protein (APP) to release Aß peptides. While PS plays an essential role in the protection of neuronal survival, PSEN mutations also increase the ratio of Aß42/Aß40. Thus, it remains unresolved whether PSEN mutations cause AD via a loss of its essential function or increases of Aß42/Aß40. Here, we test whether the knockin (KI) allele of Psen1 L435F, the most severe FAD mutation located closest to the active site of γ-secretase, causes age-dependent cortical neurodegeneration independent of Aß by crossing various Psen mutant mice to the App-null background. We report that removing Aß completely through APP deficiency has no impact on the age-dependent neurodegeneration in Psen mutant mice, as shown by the absence of effects on the reduced cortical volume and decreases of cortical neurons at the ages of 12 and 18 mo. The L435F KI allele increases Aß42/Aß40 in the cerebral cortex while decreasing de novo production and steady-state levels of Aß42 and Aß40 in the presence of APP. Furthermore, APP deficiency does not alleviate elevated apoptotic cell death in the cerebral cortex of Psen mutant mice at the ages of 2, 12, and 18 mo, nor does it affect the progressive microgliosis in these mice. Our findings demonstrate that Psen1 mutations cause age-dependent neurodegeneration independent of Aß, providing further support for a loss-of-function pathogenic mechanism underlying PSEN mutations.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Corteza Cerebral , Mutación , Presenilina-1 , Presenilina-1/genética , Presenilina-1/metabolismo , Animales , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/genética , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Neuronas/metabolismo , Neuronas/patología , Ratones Transgénicos , HumanosRESUMEN
We investigate the mechanism of action of astragalin (AST) in the treatment of Alzheimer's disease (AD). Network pharmacology was conducted to analyze the relationships among AST, AD, and neuroinflammation, The APP/PS1 transgenic mice with AD were used in the experiments; to be specific, the influence of AST on the behavior of mice was analyzed by Morris water maze and eight-arm radial maze tests, the tissue inflammatory factor levels were detected by ELISA, and pathological changes were analyzed by H&E and immunohistochemical staining. Analysis results of network pharmacology suggested that AST exerted the multi-target effect on neuroinflammation in AD. Through molecular docking and dynamics analyses, COX2 might be the target of AST. Moreover, animal experimental results demonstrated that AST improved the behavior of AD mice, and enhanced the motor and memory abilities, meanwhile, it suppressed the expression of inflammatory factors in tissues and the activation of microglial cells. this study discovers that AST can suppress microglial cell activation via COX2 to improve neuroinflammation in AD.
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Enfermedad de Alzheimer , Quempferoles , Ratones Transgénicos , Simulación del Acoplamiento Molecular , Farmacología en Red , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ratones , Quempferoles/farmacología , Quempferoles/uso terapéutico , Aprendizaje por Laberinto/efectos de los fármacos , Masculino , Ciclooxigenasa 2/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark amyloid-ß pathology.
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Transportador 1 de Casete de Unión a ATP , Enfermedad de Alzheimer , Apolipoproteína E3 , Apolipoproteína E4 , Modelos Animales de Enfermedad , Ratones Transgénicos , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Humanos , Ratones , Apolipoproteína E4/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Receptores X del Hígado/agonistas , Receptores X del Hígado/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Seizures are increasingly being recognized as the hallmark of Alzheimer's disease (AD). Neuronal hyperactivity can be a consequence of neuronal damage caused by abnormal amyloid ß (Aß) depositions. However, it can also be a cell-autonomous phenomenon causing AD by Aß-independent mechanisms. Various studies using animal models have shown that Ca2+ is released from the endoplasmic reticulum (ER) via type 1 inositol triphosphate receptors (InsP3R1s) and ryanodine receptors (RyRs). To investigate which is the main pathophysiological mechanism in human neurons, we measured Ca2+ signaling in neural cells derived from three early-onset AD patients harboring Presenilin-1 variants (PSEN1 p.A246E, p.L286V, and p.M146L). Of these, it has been reported that PSEN1 p.A246E and p.L286V did not produce a significant amount of abnormal Aß. We found all PSEN1-mutant neurons, but not wild-type, caused abnormal Ca2+-bursts in a manner dependent on the calcium channel, Ryanodine Receptor 2 (RyR2). Indeed, carvedilol, an RyR2 inhibitor, and VK-II-86, an analog of carvedilol without the ß-blocking effects, sufficiently eliminated the abnormal Ca2+ bursts. In contrast, Dantrolene, an inhibitor of RyR1 and RyR3, and Xestospongin c, an IP3R inhibitor, did not attenuate the Ca2+-bursts. The Western blotting showed that RyR2 expression was not affected by PSEN1 p.A246E, suggesting that the variant may activate the RyR2. The RNA-Seq data revealed that ER-stress responsive genes were increased, and mitochondrial Ca2+-transporter genes were decreased in PSEN1A246E cells compared to the WT neurons. Thus, we propose that aberrant Ca2+ signaling is a key link between human pathogenic PSEN1 variants and cell-intrinsic hyperactivity prior to deposition of abnormal Aß, offering prospects for the development of targeted prevention strategies for at-risk individuals.
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Enfermedad de Alzheimer , Señalización del Calcio , Calcio , Carvedilol , Neuronas , Presenilina-1 , Canal Liberador de Calcio Receptor de Rianodina , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Presenilina-1/genética , Presenilina-1/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/genética , Carvedilol/farmacologíaRESUMEN
SIL1, an endoplasmic reticulum (ER)-resident protein, is reported to play a protective role in Alzheimer's disease (AD). However, the effect of SIL1 on amyloid precursor protein (APP) processing remains unclear. In this study, the role of SIL1 in APP processing was explored both in vitro and in vivo. In the in vitro experiment, SIL1 was either overexpressed or knocked down in cells stably expressing the human Swedish mutant APP695. In the in vivo experiment, AAV-SIL1-EGFP or AAV-EGFP was microinjected into APP23/PS45 mice and their wild-type littermates. Western blotting (WB), immunohistochemistry, RNA sequencing (RNA-seq), and behavioral experiments were performed to evaluate the relevant parameters. Results indicated that SIL1 expression decreased in APP23/PS45 mice. Overexpression of SIL1 significantly decreased the protein levels of APP, presenilin-1 (PS1), and C-terminal fragments (CTFs) of APP in vivo and in vitro. Conversely, knockdown of SIL1 increased the protein levels of APP, ß-site APP cleavage enzyme 1 (BACE1), PS1, and CTFs, as well as APP mRNA expression in 2EB2 cells. Furthermore, SIL1 overexpression reduced the number of senile plaques in APP23/PS45 mice. Importantly, Y-maze and Morris Water maze tests demonstrated that SIL1 overexpression improved cognitive impairment in APP23/PS45 mice. These findings indicate that SIL1 improves cognitive impairment in APP23/PS45 mice by inhibiting APP amyloidogenic processing and suggest that SIL1 is a potential therapeutic target for AD by modulating APP processing.
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Precursor de Proteína beta-Amiloide , Disfunción Cognitiva , Ratones Transgénicos , Animales , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Ratones , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/genética , Péptidos beta-Amiloides/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Regulación de la Expresión Génica , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , HumanosRESUMEN
Accumulating evidence implicates that herpes simplex virus type 1 (HSV-1) has been linked to the development and progression of Alzheimer's disease (AD). HSV-1 infection induces ß-amyloid (Aß) deposition in vitro and in vivo, but the effect and precise mechanism remain elusive. Here, we show that HSV-1 infection of the brains of transgenic 5xFAD mice resulted in accelerated Aß deposition, gliosis, and cognitive dysfunction. We demonstrate that HSV-1 infection induced the recruitment of microglia to the viral core to trigger microglial phagocytosis of HSV-GFP-positive neuronal cells. In addition, we reveal that the NLRP3 inflammasome pathway induced by HSV-1 infection played a crucial role in Aß deposition and the progression of AD caused by HSV-1 infection. Blockade of the NLRP3 inflammasome signaling reduces Aß deposition and alleviates cognitive decline in 5xFAD mice after HSV-1 infection. Our findings support the notion that HSV-1 infection is a key factor in the etiology of AD, demonstrating that NLRP3 inflammasome activation functions in the interface of HSV-1 infection and Aß deposition in AD.
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Enfermedad de Alzheimer , Progresión de la Enfermedad , Herpesvirus Humano 1 , Ratones Transgénicos , Microglía , Proteína con Dominio Pirina 3 de la Familia NLR , Fagocitosis , Transducción de Señal , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/virología , Ratones , Microglía/metabolismo , Microglía/patología , Microglía/virología , Transducción de Señal/fisiología , Humanos , Herpes Simple/patología , Herpes Simple/inmunología , Herpes Simple/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Modelos Animales de Enfermedad , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
BACKGROUND: Physical exercise has been shown to be beneficial for individuals with Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. METHODS: Six-month-old Amyloid precursor protein/Presenilin 1 (APP/PS1) transgenic (Tg) mice and wild-type (Wt) mice were randomly assigned to either a sedentary group (Tg-Sed, Wt-Sed) or an exercise group (Tg-Ex, Wt-Ex) undertaking a 12-week, moderate-intensity treadmill running program. Consequently, all mice were tested for memory function and amyloid ß (Aß) levels and phosphorylation of tau and protein kinase B (Akt)/glycogen synthase kinase-3 (GSK3) were examined in tissues of both the cortex and hippocampus. RESULTS: Tg-Sed mice had severely impaired memory, higher levels of Aß, and increased phosphorylation of tau, GSK3α tyrosine279, and GSK3ß tyrosine216, but less phosphorylation of GSK3α serine21, GSK3ß serine9, and Akt serine473 in both tissues than Wt-Sed mice in respective tissues. Tg-Ex mice showed significant improvement in memory function along with lower levels of Aß and less phosphorylation of tau (both tissues), GSK3α tyrosine279 (both tissues), and GSK3ß tyrosine216 (hippocampus only), but increased phosphorylation of GSK3α serine21 (both tissues), GSK3ß serine9 (hippocampus only), and Akt serine473 (both tissues) compared with Tg-Sed mice in respective tissues. CONCLUSIONS: Moderate-intensity aerobic exercise is highly effective in improving memory function in 9-month-old APP/PS1 mice, most likely through differential modulation of GSK3α/ß phosphorylation in the cortex and hippocampus.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Corteza Cerebral , Glucógeno Sintasa Quinasa 3 beta , Glucógeno Sintasa Quinasa 3 , Hipocampo , Condicionamiento Físico Animal , Presenilina-1 , Animales , Masculino , Ratones , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo/metabolismo , Ratones Transgénicos , Fosforilación , Condicionamiento Físico Animal/fisiología , Presenilina-1/genética , Presenilina-1/metabolismo , Proteínas tau/metabolismoRESUMEN
OBJECTIVES: To explore the pathogenesis of Alzheimer's disease (AD), the potential targets and signaling pathways of ginsenoside Rg1 against AD were investigated by network pharmacology. METHODS: Ginsenoside Rg1 targets were identified through PubChem, PharmMapper, and Uniprot databases, while the GeneCards database was used to examine the respective targets of amyloid precursor protein (APP) and AD. Then, the common targets between ginsenoside Rg1 and APP were explored by the Venny tool, the interaction network diagram between the active components and the targets was built via Cytoscape software, as well as GO enrichment and KEGG pathway annotation analysis were performed. Furthermore, genes associated with ferroptosis were found by the GeneCards and FerrDb databases. Besides, the connection among ginsenoside Rg1, APP, ferroptosis, and AD was predicted and analyzed. Finally, the effects of ginsenosides Rg1 and liproxstain-1 on the proliferation and differentiation of APP/PS1 mice were evaluated by immunohistochemistry. RESULTS: Ginsenoside Rg1, APP, ferroptosis, and AD had 12 hub genes. GO enrichment and KEGG pathway annotation analysis showed that EGFR, SRC, protein hydrolysis, protein phosphorylation, the Relaxin pathway, and the FoxO signaling pathway play an important role in the potential mechanism of ginsenoside Rg1's under regulation of ferroptosis anti-AD through the modulation of APP-related signaling pathways. The APP/PS1 mice experiment verified that ginsenosides Rg1 and liproxstain-1 can promote the proliferation and differentiation. CONCLUSION: Ginsenoside Rg1, APP and ferroptosis may act on EGFR, SRC, the Relaxin and FoxO signaling pathways to regulate protein metabolism, protein phosphorylation and other pathways to improve AD symptoms.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Ferroptosis , Ginsenósidos , Farmacología en Red , Ginsenósidos/farmacología , Ferroptosis/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Ratones , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Transducción de Señal/efectos de los fármacos , Humanos , Ratones Transgénicos , Mapas de Interacción de Proteínas/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Masculino , Modelos Animales de Enfermedad , Presenilina-1/genética , Presenilina-1/metabolismo , Ratones Endogámicos C57BLRESUMEN
Mice models of Alzheimer's disease (APP/PS1) typically experience cognitive decline with age. G6PD overexpressing mice (G6PD-Tg) exhibit better protection from age-associated functional decline including improvements in metabolic and muscle functions as well as reduced frailty compared to their wild-type counterparts. Importantly G6PD-Tg mice show diminished accumulation of DNA oxidation in the brain at different ages in both males and females. To further explore the potential benefits of modulating the G6PD activity in neurodegenerative diseases, triple transgenic mice (3xTg G6PD) were generated, overexpressing APP, PSEN1, and G6PD genes. The cognitive decline characteristic of APP/PS1 mice was prevented in 3xTg G6PD mice, despite similar amyloid-ß (Aß) levels in the hippocampus. This challenges the dominant hypothesis in Alzheimer's disease (AD) etiology and the majority of therapeutic efforts in the field, based on the notion that Aß is pivotal in cognitive preservation. Notably, the antioxidant properties of G6PD led to a decrease in oxidative stress parameters, such as improved GSH/GSSG and GSH/CysSSG ratios, without major changes in oxidative damage markers. Additionally, metabolic changes in 3xTg G6PD mice increased brain energy status, countering the hypometabolism observed in Alzheimer's models. Remarkably, a higher respiratory exchange ratio suggested increased carbohydrate utilization. The relative failures of Aß-targeted clinical trials have raised significant skepticism on the amyloid cascade hypothesis and whether the development of Alzheimer's drugs has followed the correct path. Our findings highlight the significance of targeting glucose-metabolizing enzymes rather than solely focusing on Aß in Alzheimer's research, advocating for a deeper exploration of glucose metabolism's role in cognitive preservation.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Glucosafosfato Deshidrogenasa , Presenilina-1 , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Cognición , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/genética , Modelos Animales de Enfermedad , Glucosafosfato Deshidrogenasa/metabolismo , Glucosafosfato Deshidrogenasa/genética , Hipocampo/metabolismo , Ratones Transgénicos , Estrés Oxidativo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Alzheimer's disease (AD) is a complex neurodegenerative condition with growing evidence implicating the gut microbiota in its pathogenesis. This study aimed to investigate the effects of NMN synbiotics, a combination of ß-nicotinamide mononucleotide (NMN), Lactobacillus plantarum, and lactulose, on the gut microbiota composition and metabolic profiles in APP/PS1 transgenic mice. Results demonstrated that NMN synbiotics led to a notable restructuring of the gut microbiota, with a decreased Firmicutes/Bacteroidetes ratio in the AD mice, suggesting a potential amelioration of gut dysbiosis. Alpha diversity indices indicated a reduction in microbial diversity following NMN synbiotics supplementation, while beta diversity analyses revealed a shift towards a more balanced microbial community structure. Functional predictions based on the 16S rRNA data highlighted alterations in metabolic pathways, particularly those related to amino acid and energy metabolism, which are crucial for neuronal health. The metabolomic analysis uncovered a significant impact of NMN synbiotics on the gut metabolome, with normalization of metabolic composition in AD mice. Differential metabolite functions were enriched in pathways associated with neurotransmitter synthesis and energy metabolism, pointing to the potential therapeutic effects of NMN synbiotics in modulating the gut-brain axis and synaptic function in AD. Immunohistochemical staining observed a significant reduction of amyloid plaques formed by Aß deposition in the brain of AD mice after NMN synbiotics intervention. The findings underscore the potential of using synbiotics to ameliorate the neurodegenerative processes associated with Alzheimer's disease, opening new avenues for therapeutic interventions.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Ratones Transgénicos , Simbióticos , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/dietoterapia , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/microbiología , Simbióticos/administración & dosificación , Ratones , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/metabolismo , Presenilina-1/genética , Mononucleótido de Nicotinamida/metabolismo , Masculino , Disbiosis/metabolismo , Disbiosis/microbiología , Disbiosis/dietoterapia , Disbiosis/terapiaRESUMEN
Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7-8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.
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Enfermedad de Alzheimer , Cognición , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Modelos Animales de Enfermedad , Ratones Transgénicos , Microglía , Inhibidores de Fosfodiesterasa 4 , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Cognición/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Presenilina-1/genética , Presenilina-1/metabolismo , Humanos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , MasculinoRESUMEN
Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aß) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers (APOE4) compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aß immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human APOE4 gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human APOE3 gene (APOE ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aß deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, APOE4 carriers showed elevated Aß, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to APOE3 carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.
Asunto(s)
Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Ratones Transgénicos , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Ratones , Humanos , Femenino , Masculino , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/patología , Angiopatía Amiloide Cerebral/genética , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer's disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered the identification of critical processes associated with the onset and progression of AD. While most experimental studies have focused on the effects of known factors on the development of pathological hallmarks in AD, e.g., amyloid deposition, tau protein and neurofibrillary tangles, neuroinflammation, etc., studies addressing the causative effects of lipid alterations remain largely unexplored. In the present study, we have used a multifactor approach combining diets containing different amounts of polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid phenotype of the frontal cortex in middle-aged female mice. First, we observed that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 LCPUFAs, ether-linked fatty acids, and saturates were also changed by the dietary condition, but the extent of changes was dependent on the genetic background and hormonal condition. Likewise, brain cortex phospholipids were mostly modified by the genotype (FAD>WT) with nuanced effects from dietary treatment. Cholesterol (but not sterol esters) was modified by the genotype (WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT mice). However, the effects of estrogen treatment were mostly observed in relation to phospholipid remodeling in a genotype-dependent manner. Analyses of lipid-derived variables indicate that nerve cell membrane biophysics were significantly affected by the three factors, with lower membrane microviscosity (higher fluidity) values obtained for FAD animals. In conclusion, our multifactor analyses revealed that the genotype, diet, and estrogen status modulate the lipid phenotype of the frontal cortex, both as independent factors and through their interactions. Altogether, the outcomes point to potential strategies based on dietary and hormonal interventions aimed at stabilizing the brain cortex lipid composition in Alzheimer's disease neuropathology.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Modelos Animales de Enfermedad , Estrógenos , Ácidos Grasos Omega-3 , Lóbulo Frontal , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/dietoterapia , Animales , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-3/farmacología , Ratones , Lóbulo Frontal/metabolismo , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/patología , Femenino , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Estrógenos/metabolismo , Estrógenos/farmacología , Ratones Transgénicos , Presenilina-1/genética , Presenilina-1/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , HumanosRESUMEN
Mutations in ubiquitously expressed presenilin genes (PSENs) lead to early-onset familial Alzheimer's disease (FAD), but patients carrying the mutation also suffer from heart diseases. To elucidate the cardiac myocyte specific effects of PSEN ΔE9, we studied cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) from patients carrying AD-causing PSEN1 exon 9 deletion (PSEN1 ΔE9). When compared with their isogenic controls, PSEN1 ΔE9 cardiomyocytes showed increased sarcoplasmic reticulum (SR) Ca2+ leak that was resistant to blockage of ryanodine receptors (RyRs) by tetracaine or inositol-3-reseceptors (IP3Rs) by 2-ABP. The SR Ca2+ leak did not affect electrophysiological properties of the hiPSC-CMs, but according to experiments and in silico simulations the leak induces a diastolic buildup of [Ca2+] near the perinuclear SR and reduces the releasable Ca2+ during systole. This demonstrates that PSEN1 ΔE9 induced SR Ca2+ leak has specific effects in iPSC-CMs, reflecting their unique structural and calcium signaling features. The results shed light on the physiological and pathological mechanisms of PSEN1 in cardiac myocytes and explain the intricacies of comorbidity associated with AD-causing mutations in PSEN1.
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Señalización del Calcio , Calcio , Células Madre Pluripotentes Inducidas , Mutación , Miocitos Cardíacos , Presenilina-1 , Canal Liberador de Calcio Receptor de Rianodina , Retículo Sarcoplasmático , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Miocitos Cardíacos/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Retículo Sarcoplasmático/metabolismo , Calcio/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/genéticaRESUMEN
Familial Alzheimer's disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single medication or intervention has proven fully effective thus far. Therefore, the combination of multitarget agents has been appealing as a potential therapeutic approach against FAD. Here, we investigated the potential of combining tramiprosate (TM), curcumin (CU), and the JNK inhibitor SP600125 (SP) as a treatment for FAD. The study analyzed the individual and combined effects of these two natural agents and this pharmacological inhibitor on the accumulation of intracellular amyloid beta iAß; hyperphosphorylated protein TAU at Ser202/Thr205; mitochondrial membrane potential (ΔΨm); generation of reactive oxygen species (ROS); oxidized protein DJ-1; proapoptosis proteins p-c-JUN at Ser63/Ser73, TP53, and cleaved caspase 3 (CC3); and deficiency in acetylcholine (ACh)-induced transient Ca2+ influx response in cholinergic-like neurons (ChLNs) bearing the mutation I416T in presenilin 1 (PSEN1 I416T). We found that single doses of TM (50 µM), CU (10 µM), or SP (1 µM) were efficient at reducing some, but not all, pathological markers in PSEN 1 I416T ChLNs, whereas a combination of TM, CU, and SP at a high (50, 10, 1 µM) concentration was efficient in diminishing the iAß, p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 markers by -50%, -75%, -86%, and -100%, respectively, in PSEN1 I417T ChLNs. Although combinations at middle (10, 2, 0.2) and low (5, 1, 0.1) concentrations significantly diminished p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 by -69% and -38%, -100% and -62%, -100% and -62%, respectively, these combinations did not alter the iAß compared to untreated mutant ChLNs. Moreover, a combination of reagents at H concentration was able to restore the dysfunctional ACh-induced Ca2+ influx response in PSEN 1 I416T. Our data suggest that the use of multitarget agents in combination with anti-amyloid (TM, CU), antioxidant (e.g., CU), and antiapoptotic (TM, CU, SP) actions might be beneficial for reducing iAß-induced ChLN damage in FAD.
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Enfermedad de Alzheimer , Antracenos , Curcumina , Presenilina-1 , Taurina/análogos & derivados , Curcumina/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Presenilina-1/genética , Presenilina-1/metabolismo , Antracenos/farmacología , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratones , Péptidos beta-Amiloides/metabolismo , Humanos , Proteínas tau/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Alzheimer's disease (AD) is characterized by a loss of neurons in the cortex and subcortical regions. Previously, we showed that the progressive degeneration of subcortical monoaminergic (MAergic) neurons seen in human AD is recapitulated in the APPswe/PS1ΔE9 (APP/PS) transgenic mouse model. Because degeneration of cholinergic (Ach) neurons is also a prominent feature of AD, we examined the integrity of the Ach system in the APP/PS model. The overall density of Ach fibers is reduced in APP/PS1 mice at 12 and 18 months of age but not at 4 months of age. Analysis of basal forebrain Ach neurons shows no loss of Ach neurons in the APP/PS model. Thus, since MAergic systems show overt cell loss at 18 months of age, the Ach system is less vulnerable to neurodegeneration in the APP/PS1 model. We also examined whether the proximity to Aß deposition affected the degeneration of Ach and 5-HT afferents. We found that the areas closer to the edges of compact Aß deposits exhibit a more severe loss of afferents than the areas that are more distal to Aß deposits. Collectively, the results indicate that the APP/PS model recapitulates the degeneration of multiple subcortical neurotransmitter systems, including the Ach system. In addition, the results indicate that Aß deposits cause global as well as local toxicity to subcortical afferents.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Neuronas Colinérgicas , Modelos Animales de Enfermedad , Placa Amiloide , Presenilina-1 , Animales , Humanos , Ratones , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/patología , Ratones Transgénicos , Placa Amiloide/patología , Placa Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Deposition of amyloid-ß (Aß) peptides in the brain is a hallmark of Alzheimer's disease. Aßs are generated through sequential proteolysis of the amyloid precursor protein by the γ-secretase complexes (GSECs). Aß peptide length, modulated by the Presenilin (PSEN) and APH-1 subunits of GSEC, is critical for Alzheimer's pathogenesis. Despite high relevance, mechanistic understanding of the proteolysis of Aß, and its modulation by APH-1, remain incomplete. Here, we report cryo-EM structures of human GSEC (PSEN1/APH-1B) reconstituted into lipid nanodiscs in apo form and in complex with the intermediate Aß46 substrate without cross-linking. We find that three non-conserved and structurally divergent APH-1 regions establish contacts with PSEN1, and that substrate-binding induces concerted rearrangements in one of the identified PSEN1/APH-1 interfaces, providing structural basis for APH-1 allosteric-like effects. In addition, the GSEC-Aß46 structure reveals an interaction between Aß46 and loop 1PSEN1, and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis.