Abstract
Alzheimer's disease (AD) is the most serious neurodegenerative disease worldwide and is characterized by progressive cognitive impairment and multiple neurological changes, including neuronal loss in the brain. However, there are no available drugs to delay or cure this disease. Consequently, neuronal replacement therapy may be a strategy to treat AD. Osthole (Ost), a natural coumarin derivative, crosses the blood-brain barrier and exerts strong neuroprotective effects against AD in vitro and in vivo. Recently, microRNAs (miRNAs) have demonstrated a crucial role in pathological processes of AD, implying that targeting miRNAs could be a therapeutic approach to AD. In the present study, we investigated whether Ost could enhance cell viability and prevent cell death in amyloid precursor protein (APP)-expressing neural stem cells (NSCs) as well as promote APP-expressing NSCs differentiation into more neurons by upregulating microRNA (miR)-9 and inhibiting the Notch signaling pathway in vitro. In addition, Ost treatment in APP/PS1 double transgenic (Tg) mice markedly restored cognitive functions, reduced Aβ plague production and rescued functional impairment of hippocampal neurons. The results of the present study provides evidence of the neurogenesis effects and neurobiological mechanisms of Ost against AD, suggesting that Ost is a promising drug for treatment of AD or other neurodegenerative diseases.
Highlights
Alzheimer’s disease is the most common degenerative disease that occurs during presenium and senectitide and is characterized by progressive dementia (Park et al, 2012; Gu et al, 2015)
After 3 days of transduction, strong GFP expression was observed in ∼82.3% cells transduced with both vectors, while strong amyloid precursor protein (APP) staining was visible in the APP group (Figure 2A)
APP mRNA and protein showed the highest expression in APP-expressing cells than in other groups, but the GFP group showed no difference with the Untrans group
Summary
Alzheimer’s disease is the most common degenerative disease that occurs during presenium and senectitide and is characterized by progressive dementia (Park et al, 2012; Gu et al, 2015). Current treatments for AD primarily focus on the use of actylcholinesterase inhibitors designed to inhibit the enzyme acetyl cholinesterase to elevate Ach levels (Zhang et al, 2010). These drugs are only able relieve AD symptoms and have deleterious side effects that limit success (Iqbal and Grundke-Iqbal, 2010). Previous studies have shown that Ost protects against neuronal death in APP-expressing NSCs (Yao et al, 2015), providing a potent agent for the treatment of AD
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