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Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.
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Esclerosis Amiotrófica Lateral , Autoanticuerpos , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/sangre , Humanos , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Relevancia ClínicaRESUMEN
As one of the most harmful air pollutants, fine particulate matter (PM2.5) has been implicated as a risk factor for multiple diseases, which has generated widespread public concern. Accordingly, a growing literature links PM2.5 exposure with Alzheimer's disease (AD). A critical gap in our understanding of the adverse effects of PM2.5 on AD is the mechanism triggered by PM2.5 that contributes to disease progression. Recent evidence has demonstrated that PM2.5 can activate NLRP3 inflammasome-mediated neuroinflammation. In this review, we highlight the novel evidence between PM2.5 exposure and AD incidence, which is collected and summarized from neuropathological, epidemiological, and neuroimaging studies to in-depth deciphering molecular mechanisms. First, neuropathological, epidemiological, and neuroimaging studies will be summarized. Then, the transport pathway for central nervous system delivery of PM2.5 will be presented. Finally, the role of NLRP3 inflammasome-mediated neuroinflammation in PM2.5 induced-effects on AD will be recapitulated.
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Contaminantes Atmosféricos/efectos adversos , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Material Particulado/efectos adversos , Enfermedad de Alzheimer/metabolismo , Antiinflamatorios/administración & dosificación , Antiinflamatorios/metabolismo , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to validate the reliability of the Chinese version of Addenbrooke's Cognitive Examination III (ACE-III) for detecting mild cognitive impairment. Furthermore, the present study compares the diagnostic accuracy of ACE-III with that of Montreal Cognitive Assessment (MoCA). METHODS: One hundred and twenty patients with MCI and 136 healthy controls were included in the study. All patients were evaluated by the Chinese version of ACE-III, MoCA and MMSE. RESULTS: Subjects in the control group showed better performance in ACE-III total score and its subdomain scores than those in the MCI group. There was a significantly positive correlation between ACE-III total score and MoCA score. Meanwhile, there was also a significantly positive correlation between ACE-III total score and MMSE score. For ACE-III total score, a cut-off point of 85 yielded a sensitivity of 97.3% and a specificity of 90.7%. The AUC for ACE-III total score was 0.978. For MoCA, a cut-off point of 23 yielded a sensitivity of 86.5% and a specificity of 97.7%. The AUC for MoCA was 0.961. There were no significant differences in diagnostic accuracy between ACE-III and MoCA. CONCLUSION: The present findings support that both ACE-III and MoCA are useful for detecting MCI in early stages.
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BACKGROUND: Numerous studies suggested that PM2.5 exposure was associated with increased risk of Alzheimer's disease (AD). But the precise mechanisms by which PM2.5 contributed to AD pathogenesis have not been clarified. METHODS: In the presence or absence of neurons, oligomeric amyloid beta (oAß)-primed microglia were stimulated with PM2.5. Firstly, we determined the effects of PM2.5 exposure on neuronal injury and inflammation in neurons-microglia co-cultures. Then, we examined whether NLRP3 inflammasome activation was involved in PM2.5-induced inflammation. After that, we investigated whether PM2.5 exposure increased ROS level in oAß-stimulated microglia. At last, we examined whether ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. RESULTS: In the present study, we showed that PM2.5 exposure aggravated oAß-induced neuronal injury and inflammation in neurons-microglia co-cultures via increasing IL-1ß production. Further, PM2.5-induced IL-1ß production in oAß-stimulated microglia was possibly dependent on NLRP3 inflammasome activation. Meanwhile, PM2.5 exposure increased ROS level in oAß-stimulated microglia. ROS was required for PM2.5-induced IL-1ß production and NLRP3 inflammasome activation in oAß-stimulated microglia. More importantly, ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. CONCLUSIONS: For the first time, these results suggested that the effects of PM2.5 under AD context were possibly mediated by NLRP3 inflammasome activation, which was triggered by ROS. Taken together, these findings have deepened our understanding on the role of PM2.5 in AD pathogenesis.
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Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/toxicidad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neuronas/metabolismo , Material Particulado/toxicidad , Fragmentos de Péptidos/toxicidad , Animales , Células Cultivadas , Técnicas de Cocultivo , Femenino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Tamaño de la Partícula , EmbarazoRESUMEN
OBJECTIVE: The aim of this study was to validate the reliability of the Chinese version of Addenbrooke's Cognitive Examination III (ACE-III) for detecting dementia. Furthermore, the present study compares the diagnostic accuracy of ACE-III with that of mini-mental state examination (MMSE). METHODS: One hundred seventy-seven patients with dementia and 180 healthy controls were included in the study. RESULTS: The reliability of ACE-III was very good (α-coefficient = 0.888). There was a significant negative correlation between Clinical Dementia Rating Scale score and total ACE-III score. Further, there was a positive correlation between MMSE score and total ACE-III score. Age exerted a significant effect on total ACE-III score, memory score, and language score. In the present study, the cutoff score of 83 showed a sensitivity of 91.1% and a specificity of 83.1%. CONCLUSIONS: The present findings support that the Chinese version of ACE-III is a reliable assessment tool for dementia. Copyright © 2017 John Wiley & Sons, Ltd.
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Trastornos del Conocimiento/diagnóstico , Demencia/diagnóstico , Pruebas Neuropsicológicas/normas , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Trastornos del Conocimiento/psicología , Demencia/psicología , Femenino , Humanos , Lenguaje , Masculino , Persona de Mediana Edad , Curva ROC , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND AND AIM: The severity of cerebral microbleeds (CMBs) affected the prognosis of patients with acute cerebrovascular disease. Considering the impact of CMBs on clinical decision, it is necessary to assess the risk factors of CMBs. We aimed to evaluate the independent risk factors of CMBs in patients with acute ischemic stroke of large-artery atherosclerosis. MATERIALS AND METHODS: 112 patients were enrolled in the study. The baseline information, the results of laboratory examination and cranial MRI were collected. The independent risk factors of CMBs in patients with acute ischemic stroke due to large-artery atherosclerosis were evaluated. RESULTS: CMBs were found in 56 (50%) patients. Older age and higher homocysteine (Hcy) level were associated with an elevated chance of occurrence of CMBs. Further, there was a positive correlation between CMBs grade and serum Hcy level. CONCLUSIONS: Serum Hcy level is strongly associated with the presence of CMBs in patients with acute ischemic stroke due to large-artery atherosclerosis. Serum Hcy level may be a potential therapeutic target for alleviating adverse clinical outcomes of CMBs.
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Isquemia Encefálica/etiología , Hemorragia Cerebral/etiología , Homocisteína/sangre , Hiperhomocisteinemia/complicaciones , Arteriosclerosis Intracraneal/complicaciones , Accidente Cerebrovascular/etiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Isquemia Encefálica/sangre , Isquemia Encefálica/diagnóstico por imagen , Hemorragia Cerebral/sangre , Hemorragia Cerebral/diagnóstico por imagen , China , Femenino , Humanos , Hiperhomocisteinemia/sangre , Hiperhomocisteinemia/diagnóstico , Arteriosclerosis Intracraneal/sangre , Arteriosclerosis Intracraneal/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnóstico por imagen , Regulación hacia ArribaRESUMEN
BACKGROUND: The close relationship between epileptic seizure and Alzheimer's disease (AD) has been demonstrated in the past decade. Valproic acid, a traditional first-line antiepileptic drug, exerted protective effects in transgenic models of AD. It remains uncertain whether new antiepileptic drugs could reverse neuropathology and behavioral deficits in AD transgenic mice. AIMS: APPswe/PS1dE9 transgenic mice were used in this study, which over express the Swedish mutation of amyloid precursor protein together with presenilin 1 deleted in exon 9. 7-month-old APPswe/PS1dE9 transgenic mice were treated daily with 20 mg/kg topiramate (TPM) and 50 mg/kg levetiracetam (LEV) for 30 days by intraperitoneal injection to explore the effects of TPM and LEV on the neuropathology and behavioral deficits. RESULTS: The results indicated that TPM and LEV alleviated behavioral deficits and reduced amyloid plaques in APPswe/PS1dE9 transgenic mice. TPM and LEV increased Aß clearance and up-regulated Aß transport and autophagic degradation. TPM and LEV inhibited Aß generation and suppressed γ-secretase activity. TPM and LEV inhibited GSK-3ß activation and increased the activation of AMPK/Akt activation. Further, TPM and LEV inhibited histone deacetylase activity in vivo. CONCLUSIONS: Therefore, TPM and LEV might have the potential to treat AD effectively in patient care.
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Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/prevención & control , Precursor de Proteína beta-Amiloide , Anticonvulsivantes/uso terapéutico , Fructosa/análogos & derivados , Piracetam/análogos & derivados , Presenilina-1 , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Anticonvulsivantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Línea Celular Tumoral , Fructosa/farmacología , Fructosa/uso terapéutico , Humanos , Levetiracetam , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Piracetam/farmacología , Piracetam/uso terapéutico , Presenilina-1/genética , TopiramatoRESUMEN
Amyloid beta peptide 1-15 (Aß1-15) and its derivatives have attracted the attention of the scientific community as candidate vaccines for Alzheimer's disease (AD) immunotherapy. Recent studies suggested that Aß1-42 modulated the immune system by inducing pro-inflammatory dendritic cells (DCs) with reduced antigen-presenting function. However, it remains elusive how Aß1-15 impacts DCs function. We therefore investigated the modulation by short Aß peptides of DCs from C57Bl/6J mice. Two new immunogens, a tandem repeat of two-lysine-linked Aß1-15 sequences with or without an addition of a RGD motif, were tested. Chemotaxis, endocytosis, antigen presenting function and producing cytokines were measured. Both peptides increased migration/endocytosis of immature DCs and MHC II molecule expression/alloreactive T cell activation in TNF-α-matured DCs. In addition, they exhibited decreased production of Th1/Th2 cytokines and pro-inflammatory cytokines. Overall, the two peptides demonstrated strong immunogenicity but did not stimulate pro-inflammatory pathways. These results support the use of short Aß immunogens in AD immunotherapy.
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Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Células de la Médula Ósea/metabolismo , Células Dendríticas/metabolismo , Inflamación/inmunología , Transducción de Señal/inmunología , Animales , Células de la Médula Ósea/inmunología , Células Dendríticas/inmunología , Endocitosis/inmunología , Endocitosis/fisiología , Inflamación/metabolismo , Complejo Mayor de Histocompatibilidad/inmunología , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismoAsunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antiinflamatorios/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Femenino , Estudios de Seguimiento , Humanos , Infliximab , Inyecciones Espinales , Escala del Estado Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
Recent studies suggest that brain angiotensin II (Ang II), the major effector molecule of the renin-angiotensin system, is implicated in the pathogenesis of Alzheimer's disease (AD). However, it remains unknown whether activation or blockade of the angiotensin II type 1 receptor (AT1R) has an impact on the secretion of amyloid-ß (Aß), the key molecule in the pathogenesis of AD. In this study, the cell models cultured primary hippocampal neurons and human embryonic kidney 293 cells, were transfected with AT1R and amyloid precursor protein/presenilin-1 (PS1). The effects of activation/blockade of the AT1R on Aß secretion, PS1 level and ß-/γ-secretase activity were investigated in different cells. When AT1R was stimulated with Ang II at concentrations from 10nM to 1000nM, only a tendency toward increased Aß secretion and ß-/γ-secretase activity was noticed in cultured primary hippocampal neurons. However, no significant change in soluble Aß(40) or Aß(42), the level of PS1, or secretase activity was found in the cells. Similarly, when the AT1R was blocked by losartan, no significant alteration of Aß secretion, PS1 levels or secretase activity was detected. In conclusion, this in vitro study demonstrates that Ang II does not directly affect Aß secretion or secretase activity via activation of AT1R. This study is significantly meaningful for exploring the pharmacologic mechanisms of angiotensin II receptor blockers in AD.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Angiotensina II/fisiología , Fragmentos de Péptidos/metabolismo , Receptor de Angiotensina Tipo 1/agonistas , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Animales Recién Nacidos , Células Cultivadas , Hipocampo/citología , Humanos , Losartán/farmacología , Neuronas/metabolismo , Presenilina-1/genética , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/genética , TransfecciónRESUMEN
Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Overexpression of tumor necrosis factor-α (TNF-α) occurs in the AD brain. Recent clinical studies have shown that the anti-TNF-α therapy improves cognition function of AD patients rapidly. However, the underlying mechanism remains elusive. The present study investigates the effects of intracerebroventricular injection of the monoclonal TNF-α antibody, Infliximab, on the pathological features of AD in the APP/PS1 double transgenic mice. We found that Infliximab administration reduced the levels of TNF-α, amyloid plaques, and tau phosphorylation as early as three days after daily injection of 150 µg Infliximab for three days. The number of CD11c-positive dendritic-like cells and the expression of CD11c were found to be increased concurrently after Infliximab injection. These data suggested that the CD11c-positive dendritic-like cells might contribute to the Infliximab-induced reduction of AD-like pathology. Furthermore, our results support the use of anti-TNF-α for the treatment of AD.