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Background: Interventions to prevent or attenuate cognitive decline and dementia in older adults are becoming increasingly important. Recently, cognitive training exercise can be via computer or mobile technology for independent or home use. Recent meta-analysis has reported that Computerized Cognitive Training (CCT) is effective at enhancing cognitive function in healthy older and Alzheimer's disease adults, although little is known about individual characteristics of each computerized program. Objective: We developed a new CCT named Brain Training Based on Everyday Living (BTEL) to enhance cognitive capacity for Instrumental Activities of Daily Living (IADL). We aim to evaluate the efficacy of the BTEL among cognitively healthy old individuals and to explore its concurrent validity and construct concept. Methods: We conducted a double-blind study where 106 individuals aged 65 years and older (intervenedâ=â53, controlâ=â53) worked on the active and placebo tasks three times a week over three months (clinical trial: UMIN000048730). The main results were examined using ANCOVA and calculating correlation coefficients. Results: We found no effect on total score of the three tests; however, there was significant effect for the BTEL on: recognition in MMSE, and immediate recall in HDSR. The tasks are associated with prefrontal cortex. In addition, correlations indicated that each BTEL domain had some validity as a cognitive assessment tool. Different from previous CCT, we determined the neuropsychological characteristics of specific cognitive tasks of the BTEL to a certain degree. Conclusions: We found modest efficacy of the BTEL in cognitively healthy old individuals and confirmed its concurrent validity and the conceptual construct.
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Actividades Cotidianas , Humanos , Anciano , Masculino , Femenino , Método Doble Ciego , Cognición/fisiología , Pruebas Neuropsicológicas , Anciano de 80 o más Años , Disfunción Cognitiva/psicología , Terapia Asistida por Computador/métodos , Resultado del Tratamiento , Reproducibilidad de los Resultados , Terapia Cognitivo-Conductual/métodos , Entrenamiento CognitivoRESUMEN
Recent studies have revealed that soluble amyloid-ß oligomers (AßOs) play a pathogenetic role in Alzheimer's disease (AD). Indeed, AßOs induce neurotoxic and synaptotoxic effects and are also critically involved in neuroinflammation. Oxidative stress appears to be a crucial event underlying these pathological effects of AßOs. From a therapeutic standpoint, new drugs for AD designed to remove AßOs or inhibit the formation of AßOs are currently being developed. However, it is also worth considering strategies for preventing AßO toxicity itself. In particular, small molecules with AßO toxicity-reducing activity have potential as drug candidates. Among such small molecules, those that can enhance Nrf2 and/or PPARγ activity can effectively inhibit AßO toxicity. In this review, I summarize studies on the small molecules that counteract AßO toxicity and are capable of activating Nrf2 and/or PPARγ. I also discuss how these interrelated pathways are involved in the mechanisms by which these small molecules prevent AßO-induced neurotoxicity and neuroinflammation. I propose that AßO toxicity-reducing therapy, designated ATR-T, could be a beneficial, complementary strategy for the prevention and treatment of AD.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , PPAR gamma , Factor 2 Relacionado con NF-E2 , Enfermedades NeuroinflamatoriasRESUMEN
BACKGROUND: Although a large amount of evidence has revealed that amyloid ß (Aß), especially Aß oligomers, protofibrils, and pyroglutamated Aßs, participate primarily in the pathophysiological processes of Alzheimer's disease, most clinical trials of anti-Aß antibody therapy have never acquired successful efficacy in human clinical trials, partly because peripheral administration of antibody medications was unable to deliver sufficient amounts of the molecules to the brain. Recently, we developed polymeric nanomicelles capable of passing through the blood-brain barrier that function as chaperones to deliver larger amounts of heavy molecules to the brain. Herein, we aimed to evaluate the efficacy of newly developed antibody 6H4 fragments specific to Aß oligomers encapsulated in polymeric nanomicelles on the development of Alzheimer's disease pathology in Alzheimer's disease model mice at the age of emergence of early Alzheimer's disease pathology. RESULTS: During the 10-week administration of 6H4 antibody fragments in polymeric nanomicelles, a significant reduction in the amounts of various toxic Aß species, such as Aß oligomers, toxic Aß conformers, and pyroglutamated Aßs in the brain was observed. In addition, immunohistochemistry indicated inhibition of diameters of Aß plaques, Aß-antibody immunoreactive areas, and also plaque core formation. Behavioral analysis of the mice model revealed that the 6H4 fragments-polymeric nanomicelle group was significantly better at maintaining long-term spatial reference memory in the probe and platform tests of the water maze, thereby indicating inhibition of the pathophysiological process of Alzheimer's disease. CONCLUSIONS: The results indicated that the strategy of reducing toxic Aß species in early dementia owing to Alzheimer's disease by providing sufficient antibodies in the brain may modify Alzheimer's disease progression.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Animales , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo , Barrera Hematoencefálica , Anticuerpos , Placa Amiloide , PolímerosRESUMEN
Burning mouth syndrome (BMS) is characterized by persistent oral burning sensations without corresponding organic findings. Dementia with Lewy bodies (DLB) is a common type of dementia and generally presents visual hallucination and parkinsonism as motor dysfunction besides cognitive decline. In this case report, we present a case in which DLB emerged during the treatment for BMS, with a relatively positive outcome for BMS. A 74 years-old female complained of burning pain in her mouth and a subsequent decrease in food intake. Following a diagnosis of BMS, pharmacotherapy was initiated. BMS was much improved with mirtazapine 15 mg and aripiprazole 1.0 mg, leading to the restoration of her food intake by day 180. However, BMS flared up again triggered by deteriorating physical condition of herself and that of her husband. With aripiprazole 1.5 mg and amitriptyline 25 mg, her BMS gradually improved by day 482. However, by day 510, an increase in anxiety was noted, accompanied by the occasionally misidentification of her husband on day 566. Her cognitive impairment and disorientation were also reported by her husband on the day 572, she was then immediately referred to a neurologist specialized dementia and diagnosed with DLB on the day 583. Her treatment was adjusted to include the prescription of rivastigmine which was titrated up to 9.0 mg. Considering the potential impact of amitriptyline on cognitive function, it was reduced and switched to mirtazapine; however, her oral sensations slightly got worse. Following the consultation with her neurologist, amitriptyline 10 mg was reintroduced and aripiprazole was discontinued on day 755. Remarkably, BMS gradually improved without deteriorating DLB. This case indicated the reaffirmed necessity of careful interviews for changes in daily life not only with the patients but also with their families through the medical assessments. It highlights the vigilance regarding potential cognitive decline underlying or induced as an adverse event especially when treating elderly patients with BMS. While the interaction between BMS and DLB remains unclear, this case underscores the importance of prudent diagnosis and constructing collaboration with specialists in managing BMS with the early phase of DLB.
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Recent evidence suggests that soluble amyloid-ß oligomers (AßOs) act as a key factor in the pathogenetic mechanism of Alzheimer's disease (AD). AßOs induce neurotoxic and synaptotoxic effects probably through binding to certain receptors, however it remains unclarified which receptors are most critically involved. In addition, dysregulation in glutamatergic signaling is implicated in AD. In this study, we used a rat primary cortical neuron model to investigate AßO-induced aberrations of synaptic proteins and binding of extracellular AßOs to candidate receptors in the glutamatergic system. Immunocytochemical analyses showed that both presynaptic (SNAP-25, synapsin I) and postsynaptic (spinophilin, homer 1b/c) proteins appeared to aberrantly dislocate from synapses upon AßO treatment. Double immunofluorescence staining of AßO-treated neurons without permeabilization pretreatment revealed that extracellular AßOs exist over neuronal soma and neurites and clearly colocalized with GluN1 and GluN2B subunits of NMDA receptors and metabotropic glutamate receptor 1 (mGluR1), but not with NMDA GluN2A subunits and mGluR5. AßO treatment altered neither total protein levels nor intracellular localizations of these receptors. These results suggest that extracellular AßOs specifically bind to both NMDA receptors containing GluN2B subunits and mGluR1. It is likely that binding of AßOs to these receptors induces various pathological responses, consequently leading to synaptic disruptions. Our study thus highlights the important roles of GluN2B-containing NMDA receptors and mGluR1 receptors in the synapse pathology in AD.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Neuronas/metabolismo , Ratas , Receptores de Glutamato Metabotrópico , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/fisiologíaRESUMEN
Soluble oligomeric assemblies of amyloid ß-protein (Aß), called Aß oligomers (AßOs), have been recognized as primary pathogenetic factors in the molecular pathology of Alzheimer's disease (AD). AßOs exert neurotoxicity and synaptotoxicity and play a critical role in the pathological progression of AD by aggravating oxidative and synaptic disturbances and tau abnormalities. As such, they are important therapeutic targets. From a therapeutic standpoint, it is not only important to clear AßOs or prevent their formation, it is also beneficial to reduce their neurotoxicity. In this regard, recent studies have reported that small molecules, most with antioxidative properties, show promise as therapeutic agents for reducing the neurotoxicity of AßOs. In this mini-review, we briefly review the significance of AßOs and oxidative stress in AD and summarize studies on small molecules with AßO-neurotoxicity-reducing effects. We also discuss mechanisms underlying the effects of these compounds against AßO neurotoxicity as well as their potential as drug candidates for the prevention and treatment of AD.
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OBJECTIVES: Concentrations of soluble amyloid precursor proteins-α (sAPPα) and -ß (sAPPß) in cerebrospinal fluid (CSF) may reflect the neuropathology of Alzheimer's disease (AD). We previously reported that the concentrations of both sAPPα and sAPPß were significantly higher in patients with mild cognitive impairment (MCI) due to AD (MCI-AD) than in control subjects without cognitive impairment. The present study analyzed whether these sAPPs are useful in the differential diagnosis of MCI. METHODS: A modified and sensitive method was used to analyze concentrations of sAPPα and sAPPß in CSF of patients with MCI-AD (n = 30) and MCI due to other causes (MCI-others) (n = 24). Phosphorylated tau (p-tau) and amyloid ß-protein 42 (Aß42) were also analyzed using standard methods. RESULTS: CSF concentrations of sAPPα and sAPPß were significantly higher in the MCI-AD than in the MCI-others group (p < 0.001). Furthermore, concentrations of both sAPPα and sAPPß were highly correlated with the concentration of p-tau, consistent with our previous report. CONCLUSIONS: Measurement of both sAPPs in CSF using sensitive methods can be helpful in the precise differential diagnosis of patients with MCI.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Disfunción Cognitiva , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Diagnóstico Diferencial , Humanos , Fragmentos de Péptidos , Proteínas tauRESUMEN
Lemur tail kinase 1 (LMTK1), previously called apoptosis-associated tyrosine kinase (AATYK), is an endosomal Ser/Thr kinase. We recently reported that LMTK1 regulates axon outgrowth, dendrite arborization and spine formation via Rab11-mediated vesicle transport. Rab11, a small GTPase regulating recycling endosome trafficking, is shown to be associated with late-onset Alzheimer's disease (LOAD). In fact, genome-wide association studies identified many proteins regulating vesicle transport as risk factors for LOAD. Furthermore, LMTK1 has been reported to be a risk factor for frontotemporal dementia. Then, we hypothesized that LMTK1 contributes to AD development through vesicle transport and examined the effect of LMTK1 on the cellular localization of AD-related proteins, amyloid precursor protein (APP) and ß-site APP cleaving enzyme 1 (BACE1). The ß-cleavage of APP by BACE1 is the initial and rate-limiting step in Aß generation. We found that LMTK1 accumulated BACE1, but not APP, to the perinuclear endosomal compartment, whereas the kinase-negative(kn) mutant of LMTK1A did not. The ß-C-terminal fragment was prone to increase under overexpression of LMTK1A kn. Moreover, the expression level of LMTK1A was reduced in AD brains. These results suggest the possibility that LMTK1 is involved in AD development through the regulation of the proper endosomal localization of BACE1.
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Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Endosomas/enzimología , Proteínas Tirosina Quinasas/metabolismo , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Ácido Aspártico Endopeptidasas/genética , Células CHO , Células COS , Chlorocebus aethiops , Cricetulus , Endosomas/genética , Células HEK293 , Humanos , Proteínas Tirosina Quinasas/genéticaRESUMEN
We report a case of a dialysis patient with severe aortic stenosis(AS) along with bilateral pheochromocytomas. A 52-year-old man presented with syncope and was diagnosed with severe AS. Although aortic valve replacement(AVR) was scheduled, bilateral pheochromocytomas were found during preoperative examination. There was a high possibility of developing hemodynamical crisis during AVR, and we planned to perform adrenalectomy prior to AVR. To avoid circulatory collapse just after adrenalectomy, balloon aortic valvuloplasty (BAV) was performed beforehand. Two weeks after the adrenalectomy, AVR was performed in a stable condition.
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Neoplasias de las Glándulas Suprarrenales , Estenosis de la Válvula Aórtica , Valvuloplastia con Balón , Feocromocitoma , Válvula Aórtica , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Diálisis Renal , Resultado del TratamientoRESUMEN
A 65-year-old woman with type â ¡ diabetes and unstable angina presented with chest pain due to in-stent restenosis. Her regular medication comprised an sodium-glucose co-transporter( SGLT) 2 inhibitor. Because of unstable hemodynamic status, semi-emergency coronary artery bypass grafting (CABG) was performed. Postoperatively, the cardiac and hemodynamic status stabilized, but there was progression of metabolic acidosis. Based on the presence of massive urinary ketone bodies without hyper glycosuria, the patient was diagnosed with euglycemic diabetic ketoacidosis( DKA) caused by an SGLT2 inhibitor. Ketoacidosis without elevated blood glucose( i.e., euglycemic DKA) has been reported to be associated with intake of an SGLT2 inhibitor, which promoted glucose excretion in the urine. Our patient developed euglycemic DKA due to the progression of myocardial ischemia and surgical stress. Guidelines in other countries have stipulated that SGLT2 inhibitor should be stopped 24 hours preoperatively. In our case, euglycemic DKA occurred even when the SGLT2 inhibitor was stopped for more than 24 hours preoperatively. Further studies on the withdrawal of an SGLT2 inhibitor in the appropriate perioperative period are required.
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Diabetes Mellitus Tipo 2 , Cetoacidosis Diabética , Anciano , Puente de Arteria Coronaria , Femenino , Glucosa , Humanos , Sodio , Inhibidores del Cotransportador de Sodio-Glucosa 2RESUMEN
Soluble amyloid-ß (Aß) oligomers (AßOs), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer's disease (AD). Since AßOs are a key therapeutic target, we attempted to identify natural agents that reduce AßO neurotoxicity. Using an assay system in which primary cultured neurons are treated with AßOs, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited AßO-induced caspase-3 activation. We then assessed the in vivo efficacy of tyrosol by oral administration of the compound into AD model (5XFAD) transgenic and non-transgenic mice from either 2 or 4 to 7 months of age. In both paradigms, tyrosol treatment did not affect body weights of mice. Immunohistochemical analysis revealed that the immunoreactivity of spinophilin, a dendritic synaptic protein, was significantly reduced in three hippocampal subregions of vehicle-treated AD mice compared with non-transgenic mice, which was reversed in tyrosol-treated AD mice. Tyrosol treatment also prevented the enhancement of 4-hydroxy-2-nonenal immunoreactivity in the hippocampal CA3 region of AD mice. By contrast, tyrosol administration did not affect Aß accumulation, as evaluated by immunohistochemical and biochemical analyses. Moreover, the Barnes maze test showed that tyrosol administration modestly mitigated spatial memory impairment in AD mice. These findings collectively indicate that the natural agent tyrosol protects neurons against AßO neurotoxicity in vitro and ameliorates synaptic disturbance, oxidative stress responses, and cognitive impairment in vivo. We thus suggest that tyrosol is potentially an effective, safe, and unique drug candidate for AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/metabolismo , Caspasa 3/metabolismo , Disfunción Cognitiva , Alcohol Feniletílico/análogos & derivados , Rhodiola , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Antioxidantes/farmacología , Células Cultivadas , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neurotoxinas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Alcohol Feniletílico/farmacología , Extractos Vegetales/farmacologíaRESUMEN
Abnormalities of the autophagy-lysosomal pathway (ALP) have been implicated in the pathology of Alzheimer's disease (AD). Activation of TFEB (transcription factor EB), a master regulator of the ALP, leads to ALP facilitation. The present study sought to clarify whether TFEB-mediated ALP facilitation influences the process of amyloid ß-protein (Aß) generation in neurons. TFEB was overexpressed in mature rat primary cortical neurons via recombinant adenoviruses, without (basal conditions) or with co-overexpression of wild-type amyloid precursor protein (APP) or its ß-C-terminal fragment (ß-CTF). We confirmed that TFEB overexpression upregulated the lysosomal proteins, cathepsin D and LAMP-1. In TFEB-expressing neurons, protein levels of ADAM10 were profoundly increased, whereas those of APP, BACE1, or γ-secretase complex proteins were unaffected. However, TFEB did not affect ADAM10 mRNA levels. TFEB overexpression had different effects on Aß production depending on the expression level of APP or ß-CTF: TFEB slightly decreased Aß secretion under basal conditions; clearly increased α-CTF levels and marginally increased ß-CTF levels with modest increases in secreted Aß in APP-expressing neurons; and caused a remarkable increase in ß-CTF levels with a significant increase in secreted Aß in ß-CTF-expressing neurons. Inhibition of proteasomes, but not lysosomes, markedly increased ß-CTF levels in ß-CTF-expressing neurons. These results collectively indicate that TFEB modulates Aß production not only by increasing α-secretase processing of APP through ADAM10 upregulation but also by augmenting ß-CTF levels possibly via altered proteasome-mediated catabolism. Thus, TFEB-mediated ALP enhancement appears to have dual, but opposite, effects on Aß production in neurons.
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Péptidos beta-Amiloides/metabolismo , Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Corteza Cerebral/metabolismo , Lisosomas/metabolismo , Neuronas/metabolismo , Proteína ADAM10/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Fragmentos de Péptidos/metabolismo , Cultivo Primario de Células , Complejo de la Endopetidasa Proteasomal/metabolismo , Ratas Wistar , Regulación hacia ArribaRESUMEN
BACKGROUND: Because soluble (or secreted) amyloid precursor protein-ß (sAPPß) and -α (sAPPα) possibly reflect pathological features of Alzheimer's disease (AD), they are potential biomarker candidates for dementia disorders, including AD and mild cognitive impairment (MCI) due to AD (MCI-AD). However, controversial results have been reported regarding their alterations in the cerebrospinal fluid (CSF) of AD and MCI-AD patients. In this study, we re-assessed the utility of sAPPα and sAPPß in CSF as diagnostic biomarkers of dementia disorders. METHODS: We used a modified and sensitive detection method to analyze sAPPs levels in CSF in four groups of patients: AD (N = 33), MCI-AD (N = 17), non-AD dementia (N = 27), and disease controls (N = 19). Phosphorylated tau (p-tau), total tau, and Aß42 were also analyzed using standard methods. RESULTS: A strong correlation was observed between sAPPα and sAPPß, consistent with previous reports. Both sAPPα and sAPPß were highly correlated with p-tau and total tau, suggesting that sAPPs possibly reflect neuropathological changes in the brain. Levels of sAPPα were significantly higher in MCI-AD cases compared with non-AD and disease control cases, and those of sAPPß were also significantly higher in MCI-AD and AD cases relative to other cases. A logistic regression analysis indicated that sAPPα and sAPPß have good discriminative power for the diagnosis of MCI-AD. CONCLUSIONS: Our findings collectively suggest that both sAPPs are pathologically relevant and potentially useful biomarkers for early and accurate diagnosis of dementia disorders. We also suggest that careful measurement is important in assessing the diagnostic utility of CSF sAPPs.
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Mitochondrial dysfunction is implicated in the pathological mechanism of Alzheimer's disease (AD). Amyloid ß-protein (Aß), which plays a central role in AD pathogenesis, is reported to accumulate within mitochondria. However, a question remains as to whether Aß is generated locally from amyloid precursor protein (APP) within mitochondria. We investigated this issue by analyzing the expression patterns of APP, APP-processing secretases, and APP metabolites in mitochondria separated from human neuroblastoma SH-SY5Y cells and those expressing Swedish mutant APP. APP, BACE1, and PEN-2 protein levels were significantly lower in crude mitochondria than microsome fractions while those of ADAM10 and the other γ-secretase complex components (presenilin 1, nicastrin, and APH-1) were comparable between fractions. The crude mitochondrial fraction containing substantial levels of cathepsin D, a lysosomal marker, was further separated via iodixanol gradient centrifugation to obtain mitochondria- and lysosome-enriched fractions. Mature APP, BACE1, and all γ-secretase complex components (in particular, presenilin 1 and PEN-2) were scarcely present in the mitochondria-enriched fraction, compared to the lysosome-enriched fraction. Moreover, expression of the ß-C-terminal fragment (ß-CTF) of APP was markedly low in the mitochondria-enriched fraction. Additionally, immunocytochemical analysis showed very little co-localization between presenilin 1 and Tom20, a marker protein of mitochondria. In view of the particularly low expression levels of BACE1, γ-secretase complex proteins, and ß-CTF in mitochondria, we propose that it is unlikely that Aß generation from APP occurs locally within this organelle.
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Precursor de Proteína beta-Amiloide/genética , Lisosomas/química , Mitocondrias/química , Neuronas/metabolismo , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Catepsina D/genética , Catepsina D/metabolismo , Fraccionamiento Celular , Línea Celular Tumoral , Centrifugación por Gradiente de Densidad , Endopeptidasas , Regulación de la Expresión Génica , Humanos , Lisosomas/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Mitocondrias/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Neuronas/química , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Transducción de SeñalRESUMEN
Alzheimer's disease (AD) is characterized by the accumulation of extracellular amyloid ß-protein (Aß) and intracellular hyperphosphorylated tau proteins. Recent evidence suggests that soluble Aß oligomers elicit neurotoxicity and synaptotoxicity, including tau abnormalities, and play an initiating role in the development of AD pathology. In this study, we focused on the unclarified issue of whether the neurotoxicity of Aß oligomers is a reversible process. Using a primary neuron culture model, we examined whether the neurotoxic effects induced by 2-day treatment with Aß42 oligomers (Aß-O) are reversible during a subsequent 2-day withdrawal period. Aß-O treatment resulted in activation of caspase-3 and eIF2α, effects that were considerably attenuated following Aß-O removal. Immunocytochemical analyses revealed that Aß-O induced aberrant phosphorylation and caspase-mediated cleavage of tau, both of which were mostly reversed by Aß-O removal. Furthermore, Aß-O caused intraneuronal dislocation of ß-catenin protein and a reduction in its levels, and these alterations were partially reversed upon Aß-O withdrawal. The dislocation of ß-catenin appeared to reflect synaptic disorganization. These findings indicate that removal of extracellular Aß-O can fully or partially reverse Aß-O-induced neurotoxic alterations in our neuron model. Accordingly, we propose that the induction of neurotoxicity by Aß oligomers is a reversible process, which has important implications for the development of AD therapies.
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Péptidos beta-Amiloides/toxicidad , Modelos Biológicos , Neuronas/patología , Neurotoxinas/toxicidad , Multimerización de Proteína , Animales , Caspasa 3/metabolismo , Células Cultivadas , Corteza Cerebral/patología , Factor 2 Eucariótico de Iniciación/metabolismo , Humanos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Ratas , beta Catenina/metabolismo , Proteínas tau/metabolismoRESUMEN
ß-Secretase, widely known as ß-site APP cleaving enzyme 1 (BACE1), is a membrane-associated protease that cleaves amyloid precursor protein (APP) to generate amyloid ß-protein (Aß). As this cleavage is a pathologically relevant event in Alzheimer's disease, BACE1 is considered a viable therapeutic target. BACE1 can be regulated at the transcriptional, post-transcriptional, translational, and post-translational levels. Elucidation of the regulatory pathways of BACE1 is critical, not only for understanding the pathological mechanisms of AD but also developing effective therapeutic strategies to inhibit activity of the protease. This mini-review focuses on the post-translational regulation of BACE1, as modulation at this level is closely associated with both physiological and pathological conditions. Current knowledge on the mechanisms underlying such BACE1 regulation and their implications for therapy are discussed.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Regulación de la Expresión Génica , Humanos , Procesamiento Proteico-PostraduccionalRESUMEN
BACKGROUND: ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is a membrane-bound aspartyl protease that initiates amyloid ß-protein (Aß) generation. Aberrant elevation of BACE1 levels in brains of Alzheimer's disease (AD) patients may involve Aß. In the present study, we used a neuron culture model system to investigate the effects of Aß on BACE1 expression as well as the underlying mechanisms. RESULTS: Rat primary cortical neurons were treated with relatively low concentrations (2.5 µM) of Aß42 oligomers (Aß-O) or fibrils (Aß-F) for 2-3 days. Aß-O induced a significant increase in protein levels of BACE1, while Aß-F only had a marginal effect. Levels of amyloid precursor protein (APP) and the major α-secretase, ADAM10, remained unaltered upon treatment with both types of Aß. Aß-O treatment resulted in activation of eIF2α and caspase 3 in a time-dependent manner, with no changes in the endoplasmic reticulum (ER) stress marker, GRP78, indicating that a typical ER stress response is not induced under our experimental conditions. Furthermore, Aß-O did not affect BACE1 mRNA expression but augmented the levels of exogenous BACE1 expressed via recombinant adenoviruses, indicating regulation of BACE1 protein expression, not at the transcriptional or translational but the post-translational level. Immunocytochemical analysis revealed that Aß-O causes a significant increase in BACE1 immunoreactivity in neurites (both axons and dendrites), but not soma of neurons; this change appears relevant to the mechanism of Aß-O-induced BACE1 elevation, which may involve impairment of BACE1 trafficking and degradation. In contrast, Aß-O had no effect on APP immunoreactivity. CONCLUSION: Our results collectively suggest that Aß oligomers induce BACE1 elevation via a post-translational mechanism involving its altered subcellular distribution in neurons, which possibly triggers a vicious cycle of Aß generation, thus contributing to the pathogenetic mechanism of AD.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Neuronas/metabolismo , Multimerización de Proteína , Procesamiento Proteico-Postraduccional , Regulación hacia Arriba , Animales , Caspasa 3/metabolismo , Células Cultivadas , Activación Enzimática , Factor 2 Eucariótico de Iniciación/metabolismo , Inmunohistoquímica , Modelos Biológicos , Transporte de Proteínas , Ratas , Fracciones Subcelulares/metabolismoRESUMEN
The ß-secretase called BACE1 is a membrane-associated protease that initiates the generation of amyloid ß-protein (Aß), a key event in Alzheimer's disease (AD). However, the mechanism of intraneuronal regulation of BACE1 is poorly understood. Here, we present evidence that low-density lipoprotein receptor-related protein 1 (LRP1), a multi-functional receptor, has a previously unrecognized function to regulate BACE1 in neurons. We show that deficiency of LRP1 exerts promotive effects on the protein expression and function of BACE1, whereas expression of LRP-L4, a functional LRP1 mini-receptor, specifically decreases BACE1 levels in both human embryonic kidney (HEK) 293 cells and rat primary neurons, leading to reduced Aß production. Our subsequent analyses further demonstrate that (1) both endogenous and exogenous BACE1 and LRP1 interact with each other and are colocalized in soma and neurites of primary neurons, (2) LRP1 reduces the protein stability and cell-surface expression of BACE1, and (3) LRP1 facilitates the shift in intracellular localization of BACE1 from early to late endosomes, thereby promoting lysosomal degradation. These findings establish that LRP1 specifically downregulates BACE1 by modulating its intraneuronal trafficking and stability through protein interaction and highlight LRP1 as a potential therapeutic target in AD.
RESUMEN
Cerebral accumulation of amyloid ß-protein (Aß) is thought to play a key role in the molecular pathology of Alzheimer's disease (AD). Three secretases (ß-, γ-, and α-secretase) are proteases that control the production of Aß from amyloid precursor protein. Increasing evidence suggests that cholesterol-rich membrane microdomains termed 'lipid rafts' are involved in the biogenesis and accumulation of Aß as well as Aß-mediated neurotoxicity. γ-Secretase is enriched in lipid rafts, which are considered an important site for Aß generation. Additionally, Aß-degrading peptidases located in lipid rafts, such as neprilysin, appear to play a role in Aß catabolism. This mini-review focuses on the roles of lipid rafts in the biogenesis and catabolism of Aß, covering recent research on the relationship between lipid rafts and the three secretases or Aß-degrading peptidases. Furthermore, the significance of lipid rafts in Aß aggregation and neurotoxicity is briefly summarized.