Abstract
Alzheimer’s disease (AD) is the most common type of dementia worldwide. The deposition of amyloid β (Aβ) is one of the most important pathological changes in AD. Autophagy, which mediates degradation of toxic proteins and maintains normal neuronal function, is dysfunctional in AD; dysfunctional autophagy is believed to be a critical pathological feature of AD. Here, we evaluated the in vitro and in vivo effects of a traditional Chinese medicinal formula called Yizhiqingxin formula (YQF) on autophagy. We determined that treatment with a high dose of YQF improved spatial memory and decreased the hippocampal Aβ burden in APP/PS1 mice, an early onset AD model. Transmission electron microscopy and immunohistochemical data revealed that YQF enhanced autophagosome formation and also increased the levels of LC3II/LC3I and Beclin1. Further, we found that YQF treatment promoted autophagic activity by inhibiting the phosphorylation of the Mammalian target of rapamycin (mTOR) at the Ser2448 site. Moreover, the level of 4EBP1 increased after YQF intervention, indicating a suppression of mTOR signaling. YQF was also found to promote autophagosome degradation, as indicated by the decreased p62 levels and increased cathepsin D and V-ATPase levels. Taken together, YQF could improve spatial learning in APP/PS1 mice and ameliorate the accumulation of Aβ while promoting autophagy via mTOR pathway modulation.
Highlights
Alzheimer’s disease (AD), manifested by core clinical features of progressive memory loss and executive dysfunction, is the most common type of dementia worldwide
The LC-MS/MS analyses of active components of Yizhiqingxin formula (YQF) in the plasma and brain tissue (Table 1 and Supplementary DataTable 1) showed that many alkaloids like berberine, palmatine, worenine, and protopine, and ginsenosides like Rg1, Re, Rb1, Rd, and Rc were found in plasma, while berberine, palmatine, epiberberine, coptisine, and ginsenoside Rb1 were found in brain tissue and ferulic acid of Conioselinum anthriscoides ‘Chuanxiong’ was found in the plasma but not brain tissue
Tau pathology and enhances cognitive functions (Caccamo et al, 2010; Majumder et al, 2011). Apart from these data, previous study reported that autophagy participates in the extracellular amyloid β (Aβ) secretion, thereby directly affecting Aβ plaque formation (Nilsson et al, 2013)
Summary
Alzheimer’s disease (AD), manifested by core clinical features of progressive memory loss and executive dysfunction, is the most common type of dementia worldwide. In China, the current prevalence of AD in people over 65 is 3.21% (Jia et al, 2014). The aggravating trend of aging population drives the increasing number of AD patients. According to the World Alzheimer Report 2018, it is estimated that there are about 47 million Alzheimer’s patients worldwide, with 10 million new cases each year (Alzheimer’s Association, 2018). Most patients eventually need constant care and help with most basic daily activities, exacting a heavy. Yizhiqingxin Modulates mTOR Signaling Pathway burden on families and society (Jia et al, 2018). AD therapy is reported to be the most expensive treatment in the U.S (Souchet et al, 2018)
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