Construction of Drug Screening Cell Model and Application to New Compounds Interfering Production and Accumulation of Beta-Amyloid by Inhibiting Gamma-Secretase

Abstract

As a result, considerable attention is being focused on attempts to develop therapies for Alzheimer's disease that are directed towards metabolic pathways that involve Abeta. One way is to reduce production of Abeta through the upstream processing enzymes (betasecretase and gamma-secretase). gamma-secretase is a multi-subunit protease complex, minimally consists of four individual proteins: presenilin, nicastrin, APH-1, and PEN-2. Consequently, several gamma-secretase inhibitors have recently been described, including transition state analogs that mimic the gamma-secretase cleavage site on the immediate Abeta precursor (C99) and presumably compete with it for binding to the gamma-secretase enzymatic site (Netzer, et al., 2003). Here express gamma-secretase's substrate (such as EGFP-tagged C99 of APP) in the cultured cells (CHO) under control of tetracycline inducible system (Tet-off system) and then evaluate the efficiency of the inhibitors by ELISA (EnzymeLinked Immunosorbnent Assay) and Western blot. This paper focuses on construction of a drug screen model for AD's gamma-secretase inhibitors and further finds some active compounds possessing gamma-secretase inhibition activity.

Systematic analysis of diabetes- and glucose metabolism-related proteins and its application to Alzheimer’s disease

“…We have previously finished construction of cell model for screening Alzheimer's drugs [10], codon usage biases in AD and other neurodegenerative diseases [11], and protein-protein interactions related to AD based on complex network [12]. Similarly, we are to propose a computational analysis on codon biases of some proteins related to diabetes and glucose metabolism, hoping that the findings might be useful for developing new therapeutic treatment for diabetes as well as AD.…”

“…Diabetes especially T2DM and AD follow the same pathological mechanisms resulting in misfolded proteins, insulin impairment, abnormal glucose metabolism, abnormal fatty acid metabolism, mitochondrial dysfunction, and high oxidative stress [1]. These shared metabolic profiles and diabetes as extreme risk factor for AD lead to the assumption that AD may reflect type-3 diabetes.We have previously finished construction of cell model for screening Alzheimer's drugs [10], codon usage biases in AD and other neurodegenerative diseases [11], and protein-protein interactions related to AD based on complex network [12]. Similarly, we are to propose a computational analysis on codon biases of some proteins related to diabetes and glucose metabolism, hoping that the findings might be useful for developing new therapeutic treatment for diabetes as well as AD.…”