RESUMEN
Alzheimer's disease (AD) is a leading cause of dementia. However, the mechanisms responsible for development of AD, especially for the sporadic variant, are still not clear. In our previous study, we discovered that a small noncoding RNA (miR-188-3p) targeting ß-site amyloid precursor protein cleaving enzyme (BACE)-1, a key enzyme responsible for Aß formation, plays an important role in the development of neuropathology in AD. In the present study, we identified that miR-338-5p, a new miRNA that also targets BACE1, contributes to AD neuropathology. We observed that expression of miR-338-5p was significantly down-regulated in the hippocampus of patients with AD and 5XFAD transgenic (TG) mice, an animal model of AD. Overexpression of miR-338-5p in the hippocampus of TG mice reduced BACE1 expression, Aß formation, and neuroinflammation. Overexpression of miR-338-5p functionally prevented impairments in long-term synaptic plasticity, learning ability, and memory retention in TG mice. In addition, we provide evidence that down-regulated expression of miR-338-5p in AD is regulated through the NF-κB signaling pathway. Our results suggest that down-regulated expression of miR-338-5p plays an important role in the development of AD.-Qian, Q., Zhang, J., He, F.-P., Bao, W.-X., Zheng, T.-T., Zhou, D.-M., Pan, H.-Y., Zhang, H., Zhang, X.-Q., He, X., Sun, B.-G., Luo, B.-Y., Chen, C., Peng, G.-P. Down-regulated expression of microRNA-338-5p contributes to neuropathology in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/genética , Hipocampo/metabolismo , MicroARNs/fisiología , Regiones no Traducidas 3' , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/biosíntesis , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/biosíntesis , Ácido Aspártico Endopeptidasas/genética , Células Cultivadas , Modelos Animales de Enfermedad , Regulación hacia Abajo , Humanos , Inflamación , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/genética , Trastornos de la Memoria/prevención & control , Ratones , Ratones Transgénicos , MicroARNs/biosíntesis , MicroARNs/genética , FN-kappa B/fisiología , Plasticidad Neuronal , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Cultivo Primario de Células , Proteínas Recombinantes/metabolismoRESUMEN
Alzheimer's disease (AD) is a most common neurodegenerative disease. The mechanisms underlying AD, especially late-onset AD, remain elusive. In the past few years, results from genome-wide association studies (GWAS) and systems approaches indicated that innate immune responses mediated by microglia played critical roles in AD. Functional analysis on animal models also showed that immune receptors or proteins expressed in microglia mediated Abeta-induced inflammation, or Abeta phagocytosis by microglia. Microglia plays double sword roles in AD. More work is warranted to elucidate the exact roles of microglia in AD, which will facilitate our better understanding of the mechanisms underlying AD.
Asunto(s)
Enfermedad de Alzheimer/patología , Microglía/fisiología , Receptores Inmunológicos/fisiología , Animales , Modelos Animales de Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Inflamación/patología , FagocitosisRESUMEN
BACKGROUND: Abnormal morphology and function of neurons in the prefrontal cortex (PFC) are associated with cognitive deficits in rodent models of Alzheimer's disease (AD), particularly in cortical layer-5 pyramidal neurons that integrate inputs from different sources and project outputs to cortical or subcortical structures. Pyramidal neurons in layer-5 of the PFC can be classified as two subtypes depending on the inducibility of prominent hyperpolarization-activated cation currents (h-current). However, the differences in the neurophysiological alterations between these two subtypes in rodent models of AD remain poorly understood. OBJECTIVE: To investigate the neurophysiological alterations between two subtypes of pyramidal neurons in hAPP-J20 mice, a transgenic model for early onset AD. METHODS: The synaptic transmission and intrinsic excitability of pyramidal neurons were investigated using whole-cell patch recordings. The morphological complexity of pyramidal neurons was detected by biocytin labelling and subsequent Sholl analysis. RESULTS: We found reduced synaptic transmission and intrinsic excitability of the prominent h-current (PH) cells but not the non-PH cells in hAPP-J20 mice. Furthermore, the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which mediated h-current was disrupted in the PH cells of hAPP-J20 mice. Sholl analysis revealed that PH cells had less dendritic intersections in hAPP-J20 mice comparing to control mice, implying that a lower morphological complexity might contribute to the reduced neuronal activity. CONCLUSION: These results suggest that the PH cells in the medial PFC may be more vulnerable to degeneration in hAPP-J20 mice and play a sustainable role in frontal dysfunction in AD.