RESUMEN
BACKGROUND: Both type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are common age-associated disorders and T2DM patients show an increased risk to suffer from AD, however, there is currently no marker to identify who in T2DM populations will develop AD. Since glycogen synthase kinase-3ß (GSK-3ß) activity, ApoE genotypes and olfactory function are involved in both T2DM and AD pathogenesis, we investigate whether alterations of these factors can identify cognitive impairment in T2DM patients. METHODS: The cognitive ability was evaluated using Minimum Mental State Examination (MMSE) and Clinical Dementia Rating (CDR), and the mild cognitive impairment (MCI) was diagnosed by Petersen's criteria. GSK-3ß activity in platelet, ApoE genotypes in leucocytes and the olfactory function were detected by Western/dot blotting, the amplification refractory mutation system (ARMS) PCR and the Connecticut Chemosensory Clinical Research Center (CCCRC) test, respectively. The odds ratio (OR) and 95% confidence intervals (95% CI) of the biomarkers for MCI diagnosis were calculated by logistic regression. The diagnostic capability of the biomarkers was evaluated by receiver operating characteristics (ROC) analyses. FINDINGS: We recruited 694 T2DM patients from Jan. 2012 to May. 2015 in 5 hospitals (Wuhan), and 646 of them met the inclusion criteria and were included in this study. 345 patients in 2 hospitals were assigned to the training set, and 301 patients in another 3 hospitals assigned to the validation set. Patients in each set were randomly divided into two groups: T2DM without MCI (termed T2DM-nMCI) or with MCI (termed T2DM-MCI). There were no significant differences for sex, T2DM years, hypertension, hyperlipidemia, coronary disease, complications, insulin treatment, HbA1c, ApoE ε2, ApoE ε3, tGSK3ß and pS9GSK3ß between the two groups. Compared with the T2DM-nMCI group, T2DM-MCI group showed lower MMSE score with older age, ApoE ε4 allele, higher olfactory score and higher rGSK-3ß (ratio of total GSK-3ß to Ser9-phosphorylated GSK-3ß) in the training set and the validation set. The OR values of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 1.09, 2.09, 1.51, 10.08 in the training set, and 1.06, 2.67, 1.47, 7.19 in the validation set, respectively. The diagnostic accuracy of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 0.76, 0.72, 0.66, 0.79 in the training set, and 0.70, 0.68, 0.73, 0.79 in the validation set, respectively. These four combined biomarkers had the area under the curve (AUC) of 82% and 86%, diagnostic accuracy of 83% and 81% in the training set and the validation set, respectively. INTERPRETATION: Aging, activation of peripheral circulating GSK-3ß, expression of ApoE ε4 and increase of olfactory score are diagnostic for the mild cognitive impairment in T2DM patients, and combination of these biomarkers can improve the diagnostic accuracy.
Asunto(s)
Enfermedad de Alzheimer/sangre , Apolipoproteína E4/sangre , Disfunción Cognitiva/sangre , Diabetes Mellitus Tipo 2/complicaciones , Glucógeno Sintasa Quinasa 3 beta/sangre , Anciano , Alelos , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Biomarcadores/sangre , Plaquetas/metabolismo , Estudios de Casos y Controles , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
The calcium/calmodulin-dependent protein kinase kinase 2, adenosine monophosphate-activated protein kinase (CAMKK2-AMPK) pathway mediated amyloid ß42 (Aß42)-induced synaptotoxicity and blockage of CAMKK2-protected neurons against the effect of Aß42. Numerous microRNAs (miRNAs) were downregulated in response to Aß42, including miR-9, a synapse-enriched miRNA that is decreased in Alzheimer's disease. In the present study the effect of miR-9 on Aß42triggered CAMKK2-AMPK activation and the synaptotoxic impairment was investigated. Aß42 oligomers were identified to be capable of inducing CAMKK2-AMPK pathway activation, which was attenuated by miR-9 overexpression. CAMKK2 was predicted to be a target of miR-9 using Pictar and Targetscan 6.2 Bioinformatics' algorithms. A luciferase activity assay and western blot analysis confirmed that miR-9 significantly inhibited CAMKK2 expression. Additionally, overexpression of miR-9 was sufficient to restore Aß42-induced dendritic spine loss and rescued Aß42-induced τ phosphorylation at Ser-262 mediated by the CAMKK2-AMPK pathway. The results of the present study demonstrated that miR-9 attenuated Aß-induced synaptotoxicity by targeting CAMKK2.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , MicroARNs/genética , Sinapsis/genética , Sinapsis/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Línea Celular , Activación Enzimática , Expresión Génica , Humanos , Ratones , Neuronas/metabolismo , Fosforilación , Biosíntesis de Proteínas , Interferencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Synaptic communication forms the basis of learning and memory. Disruptions of synaptic function and memory have been widely reported in many neurological diseases, such as dementia. Thus, restoration of impaired synaptic communication is a potential therapeutic approach for these diseases. In this study, we demonstrated that supplementation with berberine, a plant alkaloid with a long history of medicinal usage in Chinese medicine, effectively reverses the synaptic deficits induced by D-galactose. We also found that berberine rescued D-galactose-induced memory impairment and additionally rescued the mRNA and protein levels of Arc/Arg3.1, an important immediate early gene that is crucial for maintaining normal synaptic plasticity. Our study provides the first piece of evidence supporting the potential use of berberine in the treatment of neural diseases with synaptic/memory impairments.