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Developing therapeutic approaches that target neuronal differentiation will be greatly beneficial for the regeneration of neurons and synaptic networks in neurological diseases. Protein synthesis (mRNA translation) has recently been shown to regulate neurogenesis of neural stem/progenitor cells (NSPCs). However, it has remained unknown whether engineering translational machinery is a valid approach for manipulating neuronal differentiation. The present study identifies that a bivalent securinine compound SN3-L6, previously designed and synthesized by our group, induces potent neuronal differentiation through a novel translation-dependent mechanism. An isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis in Neuro-2a progenitor cells revealed that SN3-L6 upregulated a group of neurogenic transcription regulators, and also upregulated proteins involved in RNA processing, translation, and protein metabolism. Notably, puromycylation and metabolic labeling of newly synthesized proteins demonstrated that SN3-L6 induced rapid and robust activation of general mRNA translation. Importantly, mRNAs of the proneural transcription factors Foxp1, Foxp4, Hsf1, and Erf were among the targets that were translationally upregulated by SN3-L6. Either inhibition of translation or knockdown of these transcription factors blocked SN3-L6 activity. We finally confirmed that protein synthesis of a same set of transcription factors was upregulated in primary cortical NPCs. These findings together identify a new compound for translational activation and neuronal differentiation, and provide compelling evidence that reprogramming transcriptional regulation network at translational levels is a promising strategy for engineering NSPCs.

Amyloid-β (Aβ) is one of the major causative agents of Alzheimer's disease (AD), the most common neurodegenerative disorder characterized by progressive cognitive impairment. While effective drugs for AD are currently limited, identifying anti-Aβ compounds from natural products has been shown as a promising strategy which may lead to breakthroughs for new drug candidate discovery. We have previously reported that 7-(4-hydroxyphenyl)-1-phenyl-4E-hepten-3-one (AO-1), a diarylheptanoid extracted from the plant Alpinia officinarum, has strong effects on neuronal differentiation and neurite outgrowth in vitro and in vivo. The present study further uncovers that AO-1 exerts neuroprotective effects against the neurotoxicity caused by Aβ. Under the damage of Aβ oligomers, the major pathological forms of Aβ, dendrites of neurons become atrophic and simplified, but such impairments were substantially alleviated by AO-1 treatment. Moreover, AO-1 reduced apoptotic levels and oxidative stress triggered by Aβ. Further analysis showed that the anticaspase and dendrite protective effects of AO-1 were dependent on activation of phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathways. These findings collectively identify AO-1 as a beneficial compound to ameliorate the deleterious effects of Aβ on dendrite integrity and cell survival, and may provide new insights on drug discovery of AD.Key words Alzheimer's disease (AD); amyloid-β (Aβ); dendrite; mammalian target of rapamycin (mTOR); neuroprotection; phosphatidylinositol 3-kinase (PI3K) Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly which is characterized by progressive cognitive decline and movement dysfunction. Being a disease with extremely complex etiology, the accumulation of amyloid-β (Aβ) peptides is believed as a main pathogenic event that directly causes neurodegeneration. 1-3)Aβ peptides, which are normally constituted by 40-42 amino acids, are released by the aberrant cleavage of amyloid precursor protein (APP) and deposit at synapses. Aβ peptides are the major component of the senile plaques observed in AD brain. Moreover, soluble oligomers formed by aggregation of monomeric Aβ42 (1-42 a.a.) peptides are the most pathogenic forms during early progression of AD. The damaging effects of Aβ42 includes synapse loss, neurite dystrophy and dendritic simplification.4,5) Thus, one of the current efforts for drug development against AD is to generate platforms that aim at antagonizing the devastating effects of Aβ oligomers. Such approaches have been proven promising for therapeutic design and drug discovery of AD. [6][7][8] A variety of compounds derived from natural sources have been identified effective for counteracting Aβ-induced neurotoxicity.9,10) Such anti-Aβ activities could be achieved through several ways. For instance, Aβ production or aggregation is prevented, or Aβ clearance is accelerated. Moreover, Aβ-induced signaling pathways could be blocked or downregulated. A great number of natural compou...