Yung-Feng Liao｜ Institute of Cellular and Organismic Biology, Academia Sinica

1. The molecular mechanisms underlying the pathogenic activity of γ-secretase in Alzheimer’s disease.
The deposition of the amyloid-β (Aβ) peptide in neuritic plaques plays a central role in the pathogenesis of Alzheimer’s disease (AD). Aβ is generated through the proteolysis of amyloid precursor protein (APP) by the sequential actions of β- and γ-secretases. We have demonstrated that a number of inflammatory molecules can modulate γ-secretase activity through various signaling pathways. Our recent data have revealed that the protein-protein interactions between γ-secretase and its substrates could be subject to endogenous regulation mediated by intracellular signaling mediators. These newly identified endogenous modulators of γ-secretase exhibit the differential regulation in governing the γ-cleavage of APP-C99 and Notch. These γ-secretase-modulating signaling pathways could thus form intrinsic networks to regulate the substrate selectivity of γ-secretase, and be superior pharmacological targets for anti-AD therapy with minimal side effects.

2. The tumorigenesis of neuroblastoma and the differentiation of neural progenitor cells.
Neuroblastoma (NB) is a heterogeneous neoplasm, and the tumor behavior of neuroblastoma is closely associated with the histological state of differentiation. We have found a number of prognostic marker proteins in human NB tumors that are tightly associated with the histological grade of differentiation and play active roles in governing the molecular mechanisms underlying the neuronal differentiation of NB. Our studies will also shed new insight to the molecular mechanisms that govern the tumor behaviors of neuroblastoma in patients.