RESUMEN
The pathogenesis of Alzheimer's disease (AD) involves multiple contributing factors, including amyloid ß (Aß) peptide aggregation, inflammation, oxidative stress, and others. Effective therapeutic drugs for treating AD are urgently needed. SQYZ granules (SQYZ), a Chinese herbal preparation, are mainly composed of the ginsenoside Rg1, astragaloside A and baicalin, and have been widely used to treat dementias for decades in China. In this study, we found the therapeutic effects of SQYZ on the cognitive impairments in an AD mouse model, the ß-amyloid precursor protein (APP) and presenilin-1 (PS1) double-transgenic mouse, which co-expresses five familial AD mutations (5XFAD); next, we further explored the underlying mechanism and observed that after SQYZ treatment, the Aß burden and inflammatory reactions in the brain were significantly attenuated. Through a proteomic approach, we found that SQYZ regulated the expression of 27 proteins, mainly those related to neuroinflammation, stress responses and energy metabolism. These results suggested that SQYZ has the ability to improve the cognitive impairment and ameliorate the neural pathological changes in AD, and the therapeutic mechanism may be related to the modulation of multiple processes related to AD pathogenesis, especially anti-neuroinflammation, promotion of stress recovery and improvement of energy metabolism.
RESUMEN
Alzheimer's disease (AD) is characterized by progressive decline of memory and cognitive functions. Deep magnetic stimulation (DMS), a noninvasive and nonpharmacological brain stimulation, has been reported to alleviate stress-related cognitive impairment in neuropsychiatric disorders. Our previous study also discovered the preventive effect of DMS on cognitive decline in an AD mouse model. However, the underlying mechanism must be explored further. In this study, we investigated the effect of DMS on spatial learning and memory functions, neurogenesis in the dentate gyrus (DG), as well as expression and activity of the cholinergic system in a transgenic mouse model of AD (5XFAD). Administration of DMS effectively improved performance in spatial learning and memory of 5XFAD mice. Furthermore, neurogenesis in the hippocampal DG of DMS-treated 5XFAD mice was clearly enhanced. In addition, DMS significantly raised the level of acetylcholine and prevented the increase in acetylcholinesterase activity as well as the decrease in acetyltransferase activity in the hippocampus of 5XFAD mice. These findings indicate that DMS may be a promising noninvasive tool for treatment and prevention of AD cognitive impairment by promoting neurogenesis and enhancing cholinergic system function.
Asunto(s)
Acetilcolina/metabolismo , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/terapia , Magnetoterapia , Neurogénesis/fisiología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Colina O-Acetiltransferasa/metabolismo , Modelos Animales de Enfermedad , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/genética , Presenilina-1/metabolismo , Distribución Aleatoria , Aprendizaje Espacial/fisiología , Memoria Espacial/fisiologíaRESUMEN
The complex pathogenesis of Alzheimer's disease (AD) involves multiple contributing factors, including amyloid ß (Aß) peptide accumulation, inflammation and oxidative stress. Effective therapeutic strategies for AD are still urgently needed. Triptolide is the major active compound extracted from Tripterygium wilfordii Hook.f., a traditional Chinese medicinal herb that is commonly used to treat inflammatory diseases. The 5-month-old 5XFAD mice, which carry five familial AD mutations in the ß-amyloid precursor protein (APP) and presenilin-1 (PS1) genes, were treated with triptolide for 8 weeks. We observed enhanced spatial learning performances, and attenuated Aß production and deposition in the brain. Triptolide also inhibited the processing of amyloidogenic APP, as well as the expression of ßAPP-cleaving enzyme-1 (BACE1) both in vivo and in vitro. In addition, triptolide exerted anti-inflammatory and anti-oxidative effects on the transgenic mouse brain. Triptolide therefore confers protection against the effects of AD in our mouse model and is emerging as a promising therapeutic candidate drug for AD.