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.

Asunto(s)

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/metabolismo

RESUMEN

Mutations in the presenilin (PS) genes are a predominant cause of familial Alzheimer's disease (fAD). An ortholog of PS in the genetic model organism Caenorhabditis elegans (C. elegans) is sel-12. Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (Aß), however this hypothesis has been challenged by recent evidence. As C. elegans lack amyloid beta (Aß), the goal of this work was to examine Aß-independent effects of mutations in sel-12 and PS1/PS2 on behaviour and sensory neuron morphology across the lifespan in a C. elegans model. Olfactory chemotaxis experiments were conducted on sel-12(ok2078) loss-of-function mutant worms. Adult sel-12 mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype in sel-12 mutant worms is rescued by transgenic over-expression of human wild-type PS1, but not the classic fAD-associated variant PS1C410Y, when expression was driven by either the endogenous sel-12 promoter (Psel-12), a pan-neuronal promoter (Primb-1), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (Psra-6, Podr-10). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation in PS1 (PS1ΔS169) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time in sel-12 mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an Aß-independent neurodegeneration in C. elegans that was rescued by cell specific over-expression of wild-type human presenilin.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Mutación , Presenilina-1 , Animales , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales Modificados Genéticamente , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Quimiotaxis/genética , Modelos Animales de Enfermedad , Presenilina-1/genética , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/patología

RESUMEN

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 , Fosfotransferasas

Asunto(s)

Enfermedad de Alzheimer , Calcinosis , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Calcinosis/genética , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Masculino , Femenino , Persona de Mediana Edad , Presenilina-1/genética

RESUMEN

Alzheimer's disease (AD) is closely associated with the neurotoxic effects of amyloid-ß (Aß), leading to synaptic damage, neuronal loss and cognitive dysfunction. Previous in vitro studies have demonstrated the potential of corilagin to counteract Aß-induced oxidative stress, inflammatory injury, and ß-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity in Aß production. However, the in vivo protective effects of corilagin on Alzheimer's disease remain unexplored. The purpose of this study was to investigate the protective effects of corilagin on APP/PS1 mice and the underlying mechanisms. The cognitive function of the mice was assessed by step-through passive avoidance and Morris water maze tests. Nissl staining was used to evaluate neuronal damage in the hippocampus. ELISA and Western blotting analyses were used to determine the associated protein expression. Transmission electron microscopy was utilized to observe the synaptic ultrastructure of hippocampal neurons. Golgi staining was applied to assess dendritic morphology and dendritic spine density in hippocampal pyramidal neurons. Immunohistochemistry and Western blotting were performed to examine the expression of synaptic-associated proteins. The results showed that corilagin improves learning and memory in APP/PS1 mice, reduces hippocampal neuron damage, inhibits BACE1 and reduces Aß generation. It also improves synaptic plasticity and the expression of synaptic-associated proteins. Corilagin effectively reduces Aß generation by inhibiting BACE1, ultimately reducing neuronal loss and enhancing synaptic plasticity to improve synaptic transmission. This study sheds light on the potential therapeutic role of corilagin in Alzheimer's disease.

Asunto(s)

Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide , Disfunción Cognitiva , Glucósidos , Hipocampo , Taninos Hidrolizables , Ratones Transgénicos , Plasticidad Neuronal , Animales , Plasticidad Neuronal/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Taninos Hidrolizables/farmacología , Taninos Hidrolizables/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Ratones , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Glucósidos/farmacología , Glucósidos/uso terapéutico , Masculino , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Presenilina-1/genética , Modelos Animales de Enfermedad , Ácido Aspártico Endopeptidasas/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Cognición/efectos de los fármacos

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese formula Guben-Jiannao Ye (GBJNY) formula has a long history of usage in traditional Chinese medicine (TCM) for the treatment of learning and memory disorders as well as senile insomnia. This formulation is derived from Sun Simiao's five tonic pills. Furthermore, modern pharmacological investigations have revealed its ability to improve cognitive impairment and ameliorate sleep-wake circadian rhythm disorders. However, the precise mechanism underlying its efficacy remains elusive. AIM OF THE STUDY: The current research explored the modulatory effects and possible mechanisms of GBJNY in circadian rhythm sleep-wake disorders and cognitive dysfunction in Alzheimer's disease using transcriptome sequencing and experimental validation. MATERIALS AND METHODS: The LC-MS/MS tandem technology was utilized to qualitatively discern the active components present in GBJNY. The APP/PS1 mice received continuous treatment with GBJNY or Melatonin for 3 months. The learning and memory abilities of mice were assessed utilizing the Morris water maze (MWM) test, while sleep changes were studied utilizing the electroencephalogram (EEG) and electromyogram (EMG). Concurrently, mice's hippocampus clock gene rhythmicity was investigated. Subsequently, we employed HE staining, Golgi staining, and immunofluorescence to observe GBJNY's impact on synaptic damage and neuronal loss. We performed high-throughput sequencing to analyze the mRNA expression profiles of mice, aiming to identify differentially expressed genes (DEGs). Subsequently, we conducted GO and KEGG enrichment analyses to explore associated signaling pathways. Furthermore, we evaluated the expression levels of proteins involved in the PI3K/AKT/mTOR pathway and Aß deposition in the hippocampus of mice. Through this comprehensive approach, we sought to elucidate and validate the potential mechanisms of action of GBJNY in APP/PS1 mice. RESULTS: Results showed 216 DEGs. Following this, we conducted GO enrichment and KEGG pathway analyses to delve deeper into the distinctions and fundamental functions of the mRNA target genes. The enrichment analysis underscored the prominence of the PI3K/Akt/mTOR signaling pathway as the most pivotal among them. Through in vivo experiments, it was further demonstrated that the administration of GBJNY enhanced memory and learning capacities in APP/PS1 mice. Additionally, GBJNY treatment resulted in alterations in the sleep-wake circadian rhythm, characterized by reduced wakefulness and an increase in non-rapid eye movement (NREM) sleep. Moreover, alterations in the peak expression of Per1, Per2, Clock, Cry1, Cry2, and Bmal1 mRNA were noted in the hippocampus of treated mice. Particularly noteworthy were the observed reductions in amyloid-beta (Aß) deposition within the hippocampus, improvements in neuronal synaptic integrity, and upregulation of mTOR, Akt, and PI3K protein expression in the hippocampal region. These findings underscore the critical involvement of the PI3K/Akt/mTOR signaling pathway in mitigating disturbances in sleep-wake circadian rhythms. CONCLUSIONS: GBJNY enhanced the cognitive performance of APP/PS1 mice and altered clock gene expression patterns, alleviating sleep-wake circadian rhythm disruptions. The fundamental mechanism appears to be linked to the PI3K/Akt/mTOR pathway regulation, offering a foundation for potential clinical applications.

Asunto(s)

Enfermedad de Alzheimer , Ritmo Circadiano , Medicamentos Herbarios Chinos , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Medicamentos Herbarios Chinos/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Enfermedad de Alzheimer/tratamiento farmacológico , Ratones , Ritmo Circadiano/efectos de los fármacos , Sueño/efectos de los fármacos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Presenilina-1/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo

RESUMEN

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.

Asunto(s)

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 Genética

RESUMEN

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.

Asunto(s)

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 , Humanos

RESUMEN

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.

Asunto(s)

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/metabolismo

RESUMEN

Nonhuman primates (NHPs), which are closely related to humans, are useful in biomedical research, and an increasing number of NHP disease models have been reported using gene editing. However, many disease-related genes cause perinatal death when manipulated homozygously by gene editing. In addition, NHP resources, which are limited, should be efficiently used. Here, to address these issues, we developed a method of introducing heterozygous genetic modifications into common marmosets by combining Platinum transcription activator-like effector nuclease (TALEN) and a gene-editing strategy in oocytes. We succeeded in introducing the heterozygous exon 9 deletion mutation in the presenilin 1 gene, which causes familial Alzheimer's disease in humans, using this technology. As a result, we obtained animals with the expected genotypes and confirmed several Alzheimer's disease-related biochemical changes. This study suggests that highly efficient heterozygosity-oriented gene editing is possible using TALEN and oocytes and is an effective method for producing genetically modified animals.

Asunto(s)

Callithrix , Exones , Edición Génica , Heterocigoto , Presenilina-1 , Nucleasas de los Efectores Tipo Activadores de la Transcripción , Animales , Callithrix/genética , Edición Génica/métodos , Nucleasas de los Efectores Tipo Activadores de la Transcripción/genética , Presenilina-1/genética , Femenino , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/genética , Animales Modificados Genéticamente/genética , Oocitos/metabolismo

RESUMEN

Objective To explore the mechanism of fasudil improving cognitive dysfunction in amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice based on mitophagy and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway. Methods APP/PS1 mice were divided into model group and treatment group, and C57BL/6 mice were used as control group. The treatment group was given intraperitoneal injection of Fasudil (25 mg/kg) once daily for 2 months, while the control group and the model group were injected with the same volume of normal saline. The behavior of mice was detected by water maze and Y maze test; Nissl staining and neuron-specific nuclear antigen (NeuN) immunofluorescence histochemical staining were used to evaluate the number and morphology of neurons. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining was used to detect neuronal apoptosis; The expression of P62 and NLRP3 was detected by immunofluorescence histochemical staining; Real time fluorescence quantitative PCR was used to detect the mRNA expression levels of phosphatase and tensin homolog deleted on chromosome ten (PTEN) -induced putative kinase 1 (PINK1), Parkin and NLRP3; Western blot analysis was used to detect the expression of PINK1, Parkin, P62, microtubule-associated protein 1 light chain 3 (LC3), NLRP3, adapter protein apoptosis-associated speck-like protein (ASC) and interleukin-18 (IL-18). Results The results of the water maze and Y maze showed that the cognitive behavior of mice in treatment group was significantly improved, and their spatial memory and exploration abilities were significantly enhanced; The results of Nissl staining and NeuN immunofluorescence histochemical staining showed that the number of neurons and Nissl bodies were lower in the model group than that in the control group, while the morphology and number of neurons were improved after fasudil treatment. The results of TUNEL staining also showed that the number of apoptotic cells in the brain tissue of APP/PS1 mice were decreased after fasudil treatment; Compared with the control group, the expression of PINK1 and Parkin in the model group decreased, while the expression of P62, LC3, NLRP3, ASC and IL-18 increased. After treatment with fasudil, the expression of PINK1, Parkin, and LC3 increased, while the expression of P62, NLRP3, ASC, and IL-18 decreased. Conclusions Fasudil can improve the cognitive function and neuronal damage in APP/PS1 mice, and its mechanism may be related to promoting mitochondrial autophagy and inhibiting the activation of NLRP3 inflammasomes.

Asunto(s)

1-(5-Isoquinolinesulfonil)-2-Metilpiperazina , Cognición , Inflamasomas , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitofagia , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Mitofagia/efectos de los fármacos , Ratones , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Cognición/efectos de los fármacos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , Masculino , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas Quinasas

RESUMEN

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.

Asunto(s)

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/metabolismo

RESUMEN

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aß plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aß deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

Asunto(s)

Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Animales Recién Nacidos , Neuronas Colinérgicas , Ratones Endogámicos C57BL , Ratones Transgénicos , Neocórtex , Animales , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ratones , Neocórtex/metabolismo , Neocórtex/patología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Neuronas Colinérgicas/patología , Neuronas Colinérgicas/metabolismo , Presenilina-1/genética , Hipoxia-Isquemia Encefálica/patología , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia-Isquemia Encefálica/genética , Lesiones Encefálicas/patología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/genética , Colina O-Acetiltransferasa/metabolismo , Colina O-Acetiltransferasa/genética , Humanos , Masculino , Modelos Animales de Enfermedad

RESUMEN

Background: Presenilin 1 (PSEN1) is one of the genes linked to the prevalence of early onset Alzheimer's disease. In mice, inactivation of Psen1 leads to developmental defects, including vertebral malformation and neural development. However, little is known about the role of PSEN1 during the development in other species. Objective: To investigate the role of PSEN1 in vertebral development and the pathogenic mechanism of neurodegeneration using a pig model. Methods: CRISPR/Cas9 system was used to generate pigs with different mutations flanking exon 9 of PSEN1, including those with a deleted exon 9 (Δexon9). Vertebral malformations in PSEN1 mutant pigs were examined by X-ray, micro-CT and micro-MRI. Neuronal cells from the brains of PSEN1 mutant pigs were analyzed by immunoflourescence, followed by image analysis including morphometric evaluation via image J and 3D reconstruction. Results: Pigs with a PSEN1 null mutation (Δexon9-12) died shortly after birth and had significant axial skeletal defects, whereas pigs carrying at least one Δexon9 allele developed normally and remained healthy. Effects of the null mutation on abnormal skeletal development were also observed in fetuses at day 40 of gestation. Abnormal distribution of astrocytes and microglia in the brain was detected in two PSEN1 mutant pigs examined compared to age-matched control pigs. The founder pigs were bred to establish and age PSEN1ΔE9/+ pigs to study their relevance to clinical Alzheimer's diseases. Conclusions: PSEN1 has a critical role for normal vertebral development and PSEN1 mutant pigs serves as novel resources to study Alzheimer's disease.

Asunto(s)

Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Presenilina-1 , Animales , Presenilina-1/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Porcinos , Mutación/genética , Encéfalo/patología , Encéfalo/metabolismo , Animales Modificados Genéticamente , Desarrollo Óseo/genética , Columna Vertebral/patología , Columna Vertebral/anomalías

RESUMEN

Background: The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer's disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature. Objective: This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. Methods: We reviewed and integrated the published research, analyzing studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. Results: Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. Conclusions: The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD.

Asunto(s)

Enfermedad de Alzheimer , Mutación , Pruebas Neuropsicológicas , Presenilina-1 , Humanos , Presenilina-1/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Colombia , Mutación/genética , Disfunción Cognitiva/genética , Cognición/fisiología

RESUMEN

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.

Asunto(s)

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/farmacología

RESUMEN

Background: Exposure to lead (Pb) is a major public health problem that could occur through contaminated soil, air, food, or water, either during the course of everyday life, or while working in hazardous occupations. Although Pb has long been known as a neurodevelopmental toxicant in children, a recent and growing body of epidemiological research indicates that cumulative, low-level Pb exposure likely drives age-related neurologic dysfunction in adults. Environmental Pb exposure in adulthood has been linked to risk of late-onset Alzheimer's disease (AD) and dementia. Objective: Although the biological mechanism underlying this link is unknown, it has been proposed that Pb exposure may increase the risk of AD via altering the expression of AD-related genes and, possibly, by activating the molecular pathways underlying AD-related pathology. Methods: We investigated Pb exposure using a line of genetically modified mice with AD-causing knock-in mutations in the amyloid precursor protein and presenilin 1 (APPΔNL/ΔNL x PS1P264L/P264L) that had been crossed with Leprdb/db mice to impart vulnerability to vascular pathology. Results: Our data show that although Pb exposure in adult mice impairs cognitive function, this effect is not related to either an increase in amyloid pathology or to changes in the expression of common AD-related genes. Pb exposure also caused a significant increase in blood pressure, a well known effect of Pb. Interestingly, although the increase in blood pressure was unrelated to genotype, only mice that carried AD-related mutations developed cognitive dysfunction, in spite of showing no significant change in cerebrovascular pathology. Conclusions: These results raise the possibility that the increased risk of dementia associated with Pb exposure in adults may be tied to its subsequent interaction with either pre-existing or developing AD-related neuropathology.

Asunto(s)

Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Agua Potable , Plomo , Ratones Transgénicos , Presenilina-1 , Animales , Plomo/toxicidad , Plomo/sangre , Plomo/efectos adversos , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inducido químicamente , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/genética , Masculino , Modelos Animales de Enfermedad , Femenino , Ratones Endogámicos C57BL

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative process responsible for almost 70% of all cases of dementia. The clinical signs consist in progressive and irreversible loss of memory, cognitive, and behavioral functions. The main histopathological hallmark is the accumulation of amyloid-ß (Aß) peptide fibrils in the brain. To date, the origin of Aß has not been determined. Recent studies have shown that the gut microbiota produces Aß, and dysbiotic states have been identified in AD patients and animal models of AD. Starting from the hypothesis that maintaining or restoring the microbiota's eubiosis is essential to control Aß's production and deposition in the brain, we used a mixture of probiotics and prebiotics (symbiotic) to treat APPPS1 male and female mice, an animal model of AD, from 2 to 8 months of age and evaluated their cognitive performances, mucus secretion, Aß serum concentration, and microbiota composition. The results showed that the treatment was able to prevent the memory deficits, the reduced mucus secretion, the increased Aß blood levels, and the imbalance in the gut microbiota found in APPPS1 mice. The present study demonstrates that the gut-brain axis plays a critical role in the genesis of cognitive impairment, and that modulation of the gut microbiota can ameliorate AD's symptomatology.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides , Disfunción Cognitiva , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Ratones Transgénicos , Prebióticos , Probióticos , Animales , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/terapia , Enfermedad de Alzheimer/terapia , Femenino , Ratones , Masculino , Presenilina-1/genética , Eje Cerebro-Intestino , Precursor de Proteína beta-Amiloide/genética , Encéfalo/metabolismo , Cognición

RESUMEN

Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-ß (Aß) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aß peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aß and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aß filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aß filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aß filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides , Placa Amiloide , Presenilina-1 , Proteínas tau , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Humanos , Placa Amiloide/patología , Placa Amiloide/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Péptidos beta-Amiloides/metabolismo , Presenilina-1/genética , Encéfalo/patología , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Mutación , Femenino , Masculino

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated. METHODS: Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases. RESULTS: Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase. CONCLUSIONS: Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies.

Asunto(s)

Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Encéfalo , Modelos Animales de Enfermedad , Ciclo Estral , Lipidómica , Lípidos , Ratones Transgénicos , Animales , Femenino , Ciclo Estral/fisiología , Ciclo Estral/sangre , Lipidómica/métodos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/sangre , Precursor de Proteína beta-Amiloide/genética , Lípidos/sangre , Presenilina-1/genética , Ratones , Metabolismo de los Lípidos/fisiología , Ratones Endogámicos C57BL