Lectures and seminars Lecture: γ-secretase, ApoE4, and Alzheimer’s disease

Alzheimer's disease (AD) is characterized by amyloid plaques in patient brain. The primary components of the plaques are amyloid-β peptides (Aβ) of varying length, which are derived from amyloid precursor protein (APP). APP is first cleaved by β-secretase to produce the C99 fragment, which is then cleaved by γ-secretase to produce Aβ. The catalytic component of γ-secretase is presenilin 1 or 2 (PS1 or PS2). Individuals harboring mutations in PS1, PS2, or APP usually develop AD before age 65. Therefore, reducing the amount of Aβ fibrils and plaques has been an attractive strategy in clinical treatment of AD. However, anti-AD clinical trials aimed at inhibiting γ-secretase have been unsuccessful. In the first half of my presentation, I will summarize our current understanding on γ-secretase and offer potential explanations for the failed clinical trials.

In the second half of my presentation, I will discuss three isoforms of human apolipoprotein E (APOE2, APOE3, and APOE4), which only differ in two amino acid positions. ApoE4 constitutes the most important genetic risk factor for sporadic AD. We identified LilrB3 (leukocyte immunoglobulin-like receptor B3) as an APOE4-specific cell surface receptor. LilrB3 specifically recognizes APOE4, but not APOE2, both in vitro and in cells. APOE4, but not APOE2, activates human microglia cells (HMC3) in a LilrB3-dependent manner. We identified small molecules and nanobodies that are capable of blocking APOE4 binding to LilrB3. Our studies have implications for potential therapeutic treatment of diseases in which APOE4 plays a causal role.

Biography: 

Yigong Shi uses biochemical and biophysical methods to study the molecular mechanism of proteins in diverse cellular processes. He pioneered structural work on apoptosis signaling for which he received the 2014 Gregori Aminoff Prize from the Royal Swedish Academy of Sciences. He solved the first structure of the spliceosome and has in a series of landmark studies characterized its mechanism in great detail. He also solved the first structure of gamma-secretase, a key membrane protein involved in generating cytotoxic amyloid aggregates in Alzheimer disease.

Yigong Shi joined the faculty of Molecular Biology at Princeton University in 1998. In 2008 he moved to Tsinghua University and served as Dean of School of Life Sciences and Vice President. In 2018, he became the Founding President of Westlake University in Hangzhou, where he currently serves as President and Chair Professor. He is a member of Academician of the Chinese Academy of Sciences, Foreign Associate of the United States National Academy of Science and Honorary Foreign Member of the American Academy of Arts and Sciences.