An analog derived from phenylpropanoids ameliorates Alzheimer's disease-like pathology and protects mitochondrial function

Abstract

The abnormal proliferation and neurogenesis of neural progenitor cells (NPCs) is usually associated with the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). Mitochondrial stress is one of the most prominent features of AD and is thought to be involved in the impairment of the neurogenesis and proliferation of NPCs. Thus, restoring mitochondrial function by pharmaceutical intervention may alleviate disease-related defects in neurogenesis and is considered a potential therapeutic strategy for AD. In the present study, we found that the oral administration of PL201A, a designed analog of phenylpropanoids, which are a family of natural products with antiaging effects, promoted the neurogenesis and proliferation of NPCs and ameliorated cognitive impairment in a transgenic mouse model of AD. Furthermore, PL201A attenuated amyloid-β-induced mitochondrial stress and promoted NPC proliferation in vitro. Further mechanistic studies showed that PL201A restored the activation of AMP-regulated protein kinase-retinoblastoma signaling, which was suppressed by amyloid-β. Our findings suggest that PL201A may represent a promising regenerative therapeutic agent for cognitive decline in neurodegenerative diseases.

Keywords: AMPK; Alzheimer's disease; Mitochondrial dysfunction; Natural products; Neural progenitor cell proliferation; Neurogenesis.