Host: The Japanese Pharmacological Society
Name : The 95th Annual Meeting of the Japanese Pharmacological Society
Number : 95
Location : Fukuoka
Date : March 07, 2022 - March 09, 2022
Amyloid-β (Aβ) peptides are produced from the sequential cleavage of the β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Since Aβ accumulates in the brains of patients with Alzheimer's disease (AD), attempts to develop therapies based on the "amyloid hypothesis" have been made. However, many of them have now failed. Therefore, there is a need to develop a new hypothesis that complements the amyloid hypothesis. Interestingly, dysfunction of endosomes, which mediate the vesicular trafficking, has been shown to be one of the earliest pathophysiologies in AD before Aβ accumulation. So the "traffic jam hypothesis," in which vesicular traffic impairment is the trigger of AD pathogenesis, is attracting attention. However, the mechanistic details remain unclear.
We have previously shown that β-carboxyl-terminal fragment of APP (βCTF), a direct precursor of Aβ, binds to TMEM30A, a component of lipid flippases. These enzymes translocate phospholipids from the exoplasmic/luminal side to the cytoplasmic leaflet of the lipid bilayer to regulate phospholipid asymmetry, and important for regulating vesicular trafficking. We have found that binding of βCTF reduces lipid flippase activity and induces vesicular traffic impairment. Furthermore, we identified these disorders are ameliorated by the βCTF-binding peptide "T-RAP."
In this session, we will discuss the development of a method to screen therapeutic drug candidates that bind to βCTF by applying T-RAP.
