RESUMEN
We previously demonstrated that the Alzheimer's disease (AD)-like model mice, Tg2576, housed at a high ambient temperature of 30 °C for 13 months, exhibited increased body temperature, which increased amyloid-ß (Aß) levels and tau stability, leading to tau phosphorylation and ultimately inducing memory impairment. Here, we aimed to exclude the possible effect of environmental factors associated with the difference in ambient temperature (23 °C vs. 30 °C) and to further clarify the effects of elevated body temperature on AD-like pathologies. We generated uncoupling protein 1 (UCP1) deletion in Tg2576 mice, Tg2576/UCP1-/-, because UCP1 deletion mice show a sustained rise in body temperature at normal room temperature. As expected, the body temperature in Tg2576/UCP1-/- mice was higher than that in Tg2576/ UCP1+/+ mice at 23 °C, which was accompanied by upregulated Aß levels due to increased ß-secretase (BACE1) and decreased neprilysin (NEP) protein levels in the brains of Tg2576/UCP1-/- mice compared with those in the Tg2576/ UCP1+/+ mice. Elevated body temperature also increased total tau levels, leading to enhanced phosphorylation, heat shock protein induction, and activated tau kinases. Furthermore, elevated body temperature enhanced glial activation and decreased synaptic protein levels in the brain. Taken together, these findings demonstrate that elevated body temperatures exacerbate AD-like pathologies.
Asunto(s)
Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Temperatura Corporal , Proteína Desacopladora 1/metabolismo , Ratones Transgénicos , Ácido Aspártico Endopeptidasas/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Modelos Animales de EnfermedadRESUMEN
Background and Objectives: Mortality and illness due to COVID-19 have been linked to a condition known as cytokine release syndrome (CRS) that is characterized by excessive production of inflammatory cytokines, particularly interleukin-6 (IL-6). Tocilizumab (TCZ), a recent IL-6 antagonist, has been redeployed as adjunctive treatment for CRS remission in COVID-19 patients. This study aimed to determine the efficacy of Tocilizumab on patients' survival and the length of stay in hospitalized COVID-19 patients admitted to the intensive care unit. Methods: Between January 2021 and June 2021, a multicenter retrospective cohort study was carried out in six tertiary care hospitals in Egypt's governorate of Giza. Based on the use of TCZ during ICU stay, eligible patients were divided into two groups (control vs. TCZ). In-hospital mortality was the main outcome. Results: A total of 740 patient data records were included in the analysis, where 630 patients followed the routine COVID-19 protocol, while 110 patients received TCZ, need to different respiratory support after hospitalization, and inflammatory mediators such as C-reactive protein (CRP), ferritin, and Lactate dehydrogenase (LDH) showed a statistically significant difference between the TCZ group and the control group. Regarding the primary outcome (discharged alive or death) and neither the secondary outcome (length of hospital stay), there is no statistically significant difference between patients treated with TCZ and the control group. Conclusions: Our cohort of patients with moderate to severe COVID-19 did not assert a reduction in the risk of mortality or the length of stay (LOS) after TCZ administration.
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COVID-19 , Humanos , SARS-CoV-2 , Estudios Retrospectivos , Interleucina-6 , Tratamiento Farmacológico de COVID-19 , Hospitalización , Unidades de Cuidados IntensivosRESUMEN
BACKGROUND: Potassium octatitanate fibers (K2Oâ¢8TiO2, POT fibers) are used as an asbestos substitute. Their physical characteristics suggest that respirable POT fibers are likely to be carcinogenic in the lung and pleura. However, previous 2-year inhalation studies reported that respired POT fibers had little or no carcinogenic potential. In the present study ten-week old male F344 rats were left untreated or were administered vehicle, 0.25 or 0.5 mg rutile-type nano TiO2 (r-nTiO2), 0.25 or 0.5 mg POT fibers, or 0.5 mg MWCNT-7 by intra-tracheal intra-pulmonary spraying (TIPS), and then observed for 2 years. RESULTS: There were no differences between the r-nTiO2 and control groups. The incidence of bronchiolo-alveolar cell hyperplasia was significantly increased in the groups treated with 0.50 mg POT and 0.50 mg MWCNT-7. The overall incidence of lung tumors, however, was not increased in either the POT or MWCNT-7 treated groups. Notably, the carcinomas that developed in the POT and MWCNT-7 treated rats were accompanied by proliferative fibrous connective tissue while the carcinomas that developed in the untreated rats and the r-nTiO2 treated rats were not (carcinomas did not develop in the vehicle control rats). In addition, the carcinoma that developed in the rat treated with 0.25 mg POT was a squamous cell carcinoma, a tumor that develops spontaneously in about 1 per 1700 rats. The incidence of mesothelial cell hyperplasia was 4/17, 7/16, and 10/14 and the incidence of malignant mesothelioma was 3/17, 1/16, and 2/14 in the 0.25 mg POT, 0.5 mg POT, and MWCNT-7 treated groups, respectively. Neither mesothelial cell hyperplasia nor mesothelioma developed in control rats or the rats treated with r-nTiO2. Since the incidence of spontaneously occurring malignant mesothelioma in rats is extremely low, approximately 1 per 1000 animals (Japan Bioassay Research Center [JBRC] historical control data), the development of multiple malignant mesotheliomas in the POT and MWCNT-7 treated groups was biologically significant. CONCLUSION: The incidence of pleural mesotheliomas in male F344 rats administered POT fibers and MWCNT-7 was significantly higher than the JBRC historical control data, indicating that the incidence of pleural mesothelioma in the groups administered POT fibers and MWCNT-7 fibers via the airway using TIPS was biologically significant. The incidence of type II epithelial cell hyperplasia and the histology of the carcinomas that developed in the POT treated rats also indicates that respirable POT fibers are highly likely to be carcinogenic in the lungs of male F344 rats.
Asunto(s)
Carcinógenos/toxicidad , Neoplasias Pulmonares/inducido químicamente , Pulmón/efectos de los fármacos , Mesotelioma/inducido químicamente , Pleura/efectos de los fármacos , Titanio/toxicidad , Animales , Carcinógenos/química , Carcinógenos/farmacocinética , Exposición por Inhalación , Pulmón/patología , Neoplasias Pulmonares/patología , Masculino , Mesotelioma/patología , Mesotelioma Maligno , Fibras Minerales , Pleura/patología , Ratas Endogámicas F344 , Propiedades de Superficie , Distribución Tisular , Titanio/química , Titanio/farmacocinéticaRESUMEN
Potassium octatitanate (K2O·8TiO2, POT) fibers are used as an alternative to asbestos. Their shape and biopersistence suggest that they are possibly carcinogenic. However, inhalation studies have shown that respired POT fibers have little carcinogenic potential. We conducted a short-term study in which we administered POT fibers, and anatase and rutile titanium dioxide nanoparticles (a-nTiO2, r-nTiO2) to rats using intra-tracheal intra-pulmonary spraying (TIPS). We found that similarly to other materials, POT fibers were more toxic than non-fibrous nanoparticles of the same chemical composition, indicating that the titanium dioxide composition of POT fibers does not appear to account for their lack of carcinogenicity. The present report describes the results of the 3-week and 52-week interim killing of our current 2-year study of POT fibers, with MWCNT-7 as a positive control and r-nTiO2 as a non-fibrous titanium dioxide control. Male F344 rats were administered 0.5 ml vehicle, 62.5 µg/ml and 125 µg/ml r-nTiO2 and POT fibers, and 125 µg/ml MWCNT-7 by TIPS every other day for 2 weeks (eight doses: total doses of 0.25 and 0.50 mg/rat). At 1 year, POT and MWCNT-7 fibers induced significant increases in alveolar macrophage number, granulation tissue in the lung, bronchiolo-alveolar cell hyperplasia and thickening of the alveolar wall, and pulmonary 8-OHdG levels. The 0.5 mg POT- and the MWCNT-7-treated groups also had increased visceral and parietal pleura thickness, increased mesothelial cell PCNA labeling indices, and a few areas of visceral mesothelial cell hyperplasia. In contrast, in the r-nTiO2-treated groups, none of the measured parameters were different from the controls.
Asunto(s)
Pulmón/efectos de los fármacos , Nanopartículas/toxicidad , Nanotubos de Carbono/toxicidad , Pleura/efectos de los fármacos , Titanio/toxicidad , Animales , Exposición por Inhalación , Pulmón/metabolismo , Pulmón/patología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/ultraestructura , Masculino , Tamaño de los Órganos/efectos de los fármacos , Pleura/metabolismo , Pleura/patología , Ratas Endogámicas F344 , Distribución Tisular , Titanio/farmacocinéticaRESUMEN
BACKGROUND: Surgery for aortic coarctation requires special care during anesthesia due to severe pain during the lateral thoracotomy incision, intraoperative hemodynamic instability and the need for large doses of intra- and postoperative analgesics and vasodilators. Additionally, the postoperative care of patients is very important. AIMS: We aimed to compare ultrasound-guided paravertebral block performed using bupivacaine alone and bupivacaine with dexamethasone in terms of the intra- and postoperative analgesic requirements and hemodynamics, postoperative complications and ICU stay. STUDY DESIGN: This was a prospective, randomized, controlled, double-blinded study. METHODS: Fifty patients aged four to 12 months scheduled for aortic coarctation surgery were randomly divided into two equal groups (n = 25). Patients in group D (dexamethasone) received 0.5 mg/kg bupivacaine 0.25% mixed with 0.1 mg/kg dexamethasone diluted with isotonic saline and those in group C (control) received 0.5 mg/kg bupivacaine 0.25% diluted with isotonic saline (total volume 15 ml in each group). Intraoperative fentanyl consumption and hemodynamics (heart rate, arterial blood pressure) at baseline, 1 min after induction, at skin incision, after 30 min, after clamping, after declamping and at the end of the surgery were recorded, along with the objective pain score (OPS) immediately postoperatively and at 4 h, 8 h, 12 h and 24 h postoperatively and the time to the first request for pethidine. The intra- and postoperative vasodilator doses, time to extubation, ICU stay duration and postoperative complications were also recorded. RESULTS: The postoperative OPS was significantly lower at 12 and 24 h in group D than in group C. The time to the first request for analgesia was significantly longer in group D than in group C (3.9 ± 2.23 vs 8.6 ± 0.69). Additionally, the time to extubation was significantly shorter in group D. CONCLUSION: The use of dexamethasone as an adjuvant in ultrasound-guided paravertebral block in paediatric patients undergoing surgery for aortic coarctation increased the duration of postoperative analgesia with a prolonged time to the first request for analgesics It was also associated with a decreased incidence of postoperative complications. TRIAL REGISTRATION: Trial registration number: NCT03074773 . (Prospectively registered). The initial registration date was 9/3/2017.
Asunto(s)
Antiinflamatorios/administración & dosificación , Coartación Aórtica/cirugía , Bloqueo Nervioso Autónomo/métodos , Dexametasona/administración & dosificación , Dolor Postoperatorio/prevención & control , Coartación Aórtica/diagnóstico por imagen , Niño , Método Doble Ciego , Femenino , Humanos , Masculino , Dolor Postoperatorio/diagnóstico por imagen , Estudios Prospectivos , Toracotomía/efectos adversos , Toracotomía/métodos , Ultrasonografía Intervencional/métodosRESUMEN
We previously demonstrated that orally supplemented Bifidobacterium breve MCC1274 (B. breve MCC1274) mitigated Alzheimer's disease (AD) pathologies in both 7-month-old AppNL-G-F mice and wild-type mice; thus, B. breve MCC1274 supplementation might potentially prevent the progression of AD. However, the possibility of using this probiotic as a treatment for AD remains unclear. Thus, we investigated the potential therapeutic effects of this probiotic on AD using 17-month-old AppNL-G-F mice with memory deficits and amyloid beta saturation in the brain. B. breve MCC1274 supplementation ameliorated memory impairment via an amyloid-cascade-independent pathway. It reduced hippocampal and cortical levels of phosphorylated extracellular signal-regulated kinase and c-Jun N-terminal kinase as well as heat shock protein 90, which might have suppressed tau hyperphosphorylation and chronic stress. Moreover, B. breve MCC1274 supplementation increased hippocampal synaptic protein levels and upregulated neuronal activity. Thus, B. breve MCC1274 supplementation may alleviate cognitive dysfunction by reducing chronic stress and tau hyperphosphorylation, thereby enhancing both synaptic density and neuronal activity in 17-month-old AppNL-G-F mice. Overall, this study suggests that B. breve MCC1274 has anti-AD effects and can be used as a potential treatment for AD.
Asunto(s)
Enfermedad de Alzheimer , Bifidobacterium breve , Aplicaciones Móviles , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Bifidobacterium breve/metabolismo , Ratones Transgénicos , Modelos Animales de Enfermedad , Trastornos de la Memoria/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismoRESUMEN
Amyloid-ß (Aß) accumulation caused by an imbalance of the production and clearance of Aß in the brain is associated with the development of Alzheimer's disease (ad). Apolipoprotein E (ApoE) (the strongest genetic risk factor) enhances Aß clearance, preventing Aß deposition. Sirtuin 2 (Sirt2) is an NAD+-dependent histone deacetylase and its inhibition has been reported to ameliorate memory impairment in ad-like model mice. However, the role of Sirt2 in ApoE secretion is unknown. Here, we found that inhibition of Sirt2 activity in primary cultured astrocytes and BV2 cells decreased ApoE secretion, resulting in the accumulation of intracellular ApoE and inhibiting extracellular Aß degradation. However, the reduction of Sirt2 protein level by Sirt2 siRNA decreased ApoE protein level, which ultimately reduces ApoE secretion. In addition, the knockdown of Sirt2 in the HEK293-APP cells also decreased levels of intracellular ApoE leading to reduction of its secretion, which is accompanied by increased Aß levels without altering APP and APP processing enzymes. Our findings provide a novel role of Sirt2 in ApoE secretion.
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Enfermedad de Alzheimer , Sirtuina 2 , Animales , Humanos , Ratones , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Astrocitos , Encéfalo/metabolismo , Células HEK293 , Ratones Transgénicos , Microglía/metabolismo , Sirtuina 2/metabolismoRESUMEN
Probiotics improve brain function, including memory and cognition, via the microbiome-gut-brain axis. Oral administration of Bifidobacterium breve MCC1274 (B. breve MCC1274) improves cognitive function in AppNL-G-F mice and mild cognitive impairment (MCI) subjects, and mitigates Alzheimer's disease (AD)-like pathologies. However, its effects on wild-type (WT) mice have not yet been explored. Thus, the effects of B. breve MCC1274 on AD-like pathologies in two-month-old WT mice were investigated, which were orally administered B. breve MCC1274 for four months. Aß levels, amyloid precursor protein (APP), APP processing enzymes, phosphorylated tau, synaptic protein levels, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated. Data analysis was performed using Student's t-test, and normality was tested using the Shapiro-Wilk test. Oral administration of B. breve MCC1274 in WT mice decreased soluble hippocampal Aß42 levels by reducing presenilin1 protein levels, and reduced phosphorylated tau levels. It also activated the protein kinase B (Akt)/glycogen synthase kinase-3ß (GSK-3ß) pathway, which may be responsible for the reduction in presenilin1 levels and inhibition of tau phosphorylation. B. breve MCC1274 supplementation attenuated microglial activation and elevated synaptic protein levels in the hippocampus. These findings suggest that B. breve MCC1274 may mitigate AD-like pathologies in WT mice by decreasing Aß42 levels, inhibiting tau phosphorylation, attenuating neuroinflammation, and improving synaptic protein levels.
Asunto(s)
Enfermedad de Alzheimer , Bifidobacterium breve , Probióticos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Bifidobacterium breve/metabolismo , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Ratones , Ratones Transgénicos , FosforilaciónRESUMEN
BACKGROUND: We previously reported the effects of a probiotic strain, Bifidobacterium breve MCC1274, in improving cognitive function in preclinical and clinical studies. Recently, we demonstrated that supplementation of this strain led to decreased amyloid-ß production, attenuated microglial activation, and suppressed inflammation reaction in the brain of APP knock-in (AppNL - G - F) mice. OBJECTIVE: In this study, we investigated the plasma metabolites to reveal the mechanism of action of this probiotic strain in this Alzheimer's disease (AD)-like model. METHODS: Three-month-old mice were orally supplemented with B. breve MCC1274 or saline for four months and their plasma metabolites were comprehensively analyzed using CE-FTMS and LC-TOFMS. RESULTS: Principal component analysis showed a significant difference in the plasma metabolites between the probiotic and control groups (PERMANOVA, pâ=â0.03). The levels of soy isoflavones (e.g., genistein) and indole derivatives of tryptophan (e.g., 5-methoxyindoleacetic acid), metabolites with potent anti-oxidative activities were significantly increased in the probiotic group. Moreover, there were increased levels of glutathione-related metabolites (e.g., glutathione (GSSG)_divalent, ophthalmic acid) and TCA cycle-related metabolites (e.g., 2-Oxoglutaric acid, succinic acid levels) in the probiotic group. Similar alternations were observed in the wild-type mice by the probiotic supplementation. CONCLUSION: These results suggest that the supplementation of B. breve MCC1274 enhanced the bioavailability of potential anti-oxidative metabolites from the gut and addressed critical gaps in our understanding of the gut-brain axis underlying the mechanisms of the probiotic action of this strain in the improvement of cognitive function.
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Bifidobacterium breve , Animales , Bifidobacterium breve/metabolismo , Suplementos Dietéticos , Genisteína/metabolismo , Glutatión/metabolismo , Disulfuro de Glutatión/metabolismo , Indoles , Ácidos Cetoglutáricos/metabolismo , Ratones , Ácido Succínico/metabolismo , TriptófanoRESUMEN
Background: Tooth loss is closely associated with Alzheimer's disease (AD). Previously, we reported that tooth loss induced memory impairment in amyloid precursor protein knock-in mice by decreasing neuronal activity and synaptic protein levels and increasing glial activation, neuroinflammation, and pyramidal neuronal cell loss without altering amyloid-ß levels in the hippocampus. However, the effects of tooth loss in young wild-type mice have not been explored yet. Objective: We investigated the effects of tooth loss on memory impairment, neuronal activity, synaptic protein levels, glial activation, and pyramidal neuronal cell loss in young wild-type mice. Methods: Two-month-old wild-type mice were randomly divided into control and tooth loss groups. In the tooth loss group, maxillary molar teeth on both sides were extracted, whereas no teeth were extracted in the control group. Two months after tooth extraction, we performed a novel object recognition test to evaluate memory function. Glial activation, neuronal activity, synaptic protein levels, and the number of pyramidal neurons were evaluated using immunofluorescence staining, immunohistochemistry, and western blotting. Results: The tooth loss group exhibited memory impairment and decreased neuronal activity and the levels of synaptic proteins in both the hippocampus and cortex. Moreover, tooth loss increased the activation of phosphorylated c-Jun N-terminal kinase (JNK), heat shock protein 90 (HSP90), and glial activation and reduced the number of pyramidal neurons in the hippocampus. Conclusion: Tooth loss in the young wild-type mice will attenuate neuronal activity, decrease synaptic protein levels, and induce pyramidal neuronal loss, and eventually lead to memory impairment.
RESUMEN
Accumulating evidence suggests that insulin deficiency is a risk factor for Alzheimer's disease (AD); however, the underlying molecular mechanisms are not completely understood. Here, we investigated the effects of insulin deficiency on AD-like pathologies using an insulin-deficient amyloid-ß (Aß) precursor protein (APP) transgenic mouse model (Tg2576 mice). Female Tg2576 mice were injected intraperitoneally with streptozotocin (STZ) to induce insulin deficiency, and their body weights, serum glucose levels, and serum insulin levels were evaluated. STZ-treated mice showed exacerbated Aß accumulation, tau hyperphosphorylation, glial activation, neuroinflammation, and increased Sirt2 protein levels in the brain, as determined by two-dimensional gel electrophoresis (2-DE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and Western blotting. Furthermore, our in vitro experiments revealed that insulin depletion or interleukin-6 treatment increased Sirt2 protein levels in both Neuro2a and Neuro2a-P301L cells. The overexpression of Sirt2 in these cells induced tau hyperphosphorylation through extracellular signal-regulated kinase (ERK) activation. Conversely, Sirt2 knockdown reversed tau hyperphosphorylation in these cells. We showed for the first time that Sirt2 is upregulated in the brains of STZ-treated Tg2576 mice and is involved in tau phosphorylation through ERK activation. Our findings suggest that Sirt2 is a promising therapeutic target for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Cromatografía Liquida , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Insulina/metabolismo , Ratones , Ratones Transgénicos , Fosforilación , Sirtuina 2/metabolismo , Estreptozocina , Espectrometría de Masas en Tándem , Proteínas tau/metabolismoRESUMEN
Global warming is a serious public health threat to people worldwide. High body temperature is one of the important risk factors for Alzheimer's disease (AD), and the body temperature of AD patients has been found to be significantly higher than that of elderly control subjects. However, the effects of high body temperature on cognitive function and AD pathologies have not been completely elucidated. We report here that Tg2576 mice housed at a high ambient temperature of 30 °C for 13 months showed an increase in the body temperature, which is accompanied by memory impairment and an enhancement of amyloid-ß peptides (Aß) generation through the upregulation of ß-site APP cleaving enzyme 1 (BACE1) level and decrease in the level of an Aß-degrading enzyme, neprilysin (NEP) in the brain, compared with those of Tg2576 mice at 23 °C. High body temperature also increased the levels of heat shock proteins (HSPs), stress-stimulated kinases such as JNK, and total tau, leading to the enhancement of tau phosphorylation at 30 °C. Taken together, our findings suggest that high body temperature exacerbates cognitive function and AD pathologies, which provides a mechanistic insight for its prevention.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Temperatura Corporal , Encéfalo/metabolismo , Cognición , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: Probiotic supplementation reestablishes microbiome diversity and improves brain function in Alzheimer's disease (AD); their molecular mechanisms, however, have not yet been fully illustrated. OBJECTIVE: We investigated the effects of orally supplemented Bifidobacterium breve MCC1274 on cognitive function and AD-like pathologies in AppNL-G-F mice. METHODS: Three-month-old AppNL-G-F mice were orally supplemented with B. breve MCC1274 for four months. The short-term memory function was evaluated using a novel object recognition test. Amyloid plaques, amyloid-ß (Aß) levels, Aß fibril, amyloid-ß protein precursor and its processing enzymes, its metabolic products, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated by immunohistochemistry, Aß ELISA, western blotting, and immunofluorescence staining. The mRNA expression levels of pro- and anti-inflammatory cytokines were determined by qRT-PCR analysis. RESULTS: We found that the oral B. breve MCC1 274 supplementation prevented memory impairment in AppNL-G-F mice and decreased hippocampal Aß levels through the enhancement of the a-disintegrin and metalloproteinase 10 (ADAM10) level. Moreover, administration of the probiotic activated the ERK/HIF-1α signaling pathway responsible for increasing the ADAM10 level and also attenuated microglial activation, which in turn led to reduction in the mRNA expression levels of pro-inflammatory cytokines in the brain. In addition, B. breve MCC1274 supplementation increased the level of synaptic proteins in the hippocampus. CONCLUSION: Our findings support the possibility that oral B. breve MCC1274 supplementation might be used as a potential preventive therapy for AD progression.
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Péptidos beta-Amiloides/metabolismo , Bifidobacterium breve/metabolismo , Trastornos de la Memoria/prevención & control , Microglía/metabolismo , Probióticos , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Hipocampo/patología , Trastornos de la Memoria/metabolismo , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: Epidemiological studies have shown that tooth loss is associated with Alzheimer's disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. OBJECTIVE: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in AppNL-G-F mice. METHODS: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL-G-F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-ß (Aß) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aß ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. RESULTS: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. CONCLUSION: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Gliosis/metabolismo , Trastornos de la Memoria/metabolismo , Placa Amiloide/metabolismo , Pérdida de Diente/complicaciones , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Femenino , Gliosis/patología , Gliosis/psicología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Trastornos de la Memoria/patología , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Placa Amiloide/patología , Placa Amiloide/psicología , Pérdida de Diente/patologíaRESUMEN
Mitochondrial dysfunctions and oxidative stress play important roles in the early pathogenesis of Alzheimer's disease (AD), which also involves the aberrant expression levels of mitochondrial proteins. However, the molecular mechanisms underlying the aberrant expression levels of these proteins in the pathogenesis of AD are still not completely understood. Tid1 (DnaJA3/mtHsp40), a mammalian homolog of the Drosophila tumor suppressor Tid56, is reported to induce mitochondrial fragmentation associated with an increase in reactive oxygen species (ROS) levels, resulting in cell death in some cancer cells. However, the involvement of Tid1 in AD pathogenesis is as yet unknown. In this study, we found that the Tid1 protein levels were upregulated in the hippocampus of AD patients and Tg2576 mice. Our in vitro studies showed that Aß42 increased the expression levels of Tid1 in primary rat cortical neurons. The knockdown of Tid1 protected against neuronal cell death induced by Aß42, and Tid1-mediated neuronal cell death, was dependent on the increased ROS generation and caspase-3 activity. The overexpression of Tid1 in HEK293-APP cells increased the BACE1 levels, resulting in increased Aß production. Conversely, Tid1 knockdown in HEK293-APP cells and primary cultured neurons decreased Aß production through the reduction in the BACE1 levels. We also found that the overexpression of Tid1 activated c-Jun N-terminal kinase (JNK) leading to increased Aß production. Taken together, our results suggest that upregulated Tid1 levels in the hippocampus of patients with AD and Tg2576 mice induce apoptosis and increase Aß production, and Tid1 may therefore be a suitable target in therapeutic interventions for AD.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Proteínas del Choque Térmico HSP40/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/metabolismo , Humanos , Neuronas/metabolismoRESUMEN
Lactoferrin (LF) is present in senile plaques and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients and amyloid-ß protein precursor transgenic (AßPP-Tg) mice. LF has anti-inflammatory and antioxidant functions, which exert neuroprotective effects against AD. However, its effects on memory impairment and AD pathogenesis have not been fully examined. In this study, we examined the effects of LF on memory impairment and AD pathogenesis in AßPP-Tg mice (J20 mice). Nine-month-old J20 mice were fed with control, 2% lactoferrin-containing (LF), and 0.5% pepsin-hydrolyzed lactoferrin-containing (LF-hyd) diets for 3 months. We found that both the LF and LF-hyd diets attenuated memory impairment in J20 mice and decreased brain Aß40 and Aß42 levels through the inhibition of amyloidogenic processing of AßPP, as it decreased ß-site amyloid protein precursor cleaving enzyme 1 (BACE1) levels. Furthermore, we found for the first time that LF and LF-hyd treatments increased both ApoE secretion and ATP-binding cassette A1 (ABCA1) protein levels in the brains of J20 mice and in primary astrocyte cultures. Moreover, LF and LF-hyd promoted extracellular degradation of Aß in primary astrocyte cultures. These findings indicate that the reduction in Aß levels in the brains of mice fed with both the LF and LF-hyd diets may also be mediated by increased ApoE secretion and ABCA1 protein levels, which in turn leads to the enhanced degradation of Aß in the brains of J20 mice. Our findings suggest that LF and LF-hyd can be used for the treatment and/or prevention of the development of AD.