Small molecule inhibitors of apolipoprotein E4‐catalyzed amyloid‐β fibrillization as novel therapeutics for Alzheimer's disease: Development of new models and analysis methods/screening studies/platforms. (7th December 2020)

• Record Type: Journal Article
• Authors: Johnson, Noah R.; Wang, Athena Ching‐Jung; Coughlan, Christina M.; Lucero, Esteban M.; Viltz, Lisa; Allen, Cody; Markham, Neil; Chial, Heidi J.; Potter, Huntington
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.043353
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative illness initiated by fibrillization of the amyloid‐beta (Aβ) peptide in the brain. Genetic factors can increase the risk for developing AD, especially in individuals who carry the ε4 allele of the apolipoprotein E ( APOE ) gene. Having one copy of APOE4 doubles the risk for AD, whereas being homozygous for APOE4 increases the risk by greater than ten‐fold. ApoE4 acts as a catalyst to accelerate the polymerization rate of Aβ into neurotoxic oligomers and filaments; thus, inhibiting this enzymatic process is a promising therapeutic approach to preventing AD. We therefore developed an ApoE4‐Aβ fibrillization assay for high‐throughput drug screening of small molecule compounds. Method: A design of experiments (DOE) approach was employed to optimize the ApoE4‐Aβ fibrillization assay. A series of fractional factorial and surface response designs were used to determine the concentrations of Aβ, ApoE4, and thioflavin T that yielded the greatest rate and amount of Aβ fibrillization. The optimized assay was then used to screen two small molecule libraries representing more than 3, 000 compounds, most of which are drugs or natural compounds that have already been tested in humans for other indications. Hit compounds were next evaluated for cytotoxicity and inhibition of Aβ neuropathology in primary mouse neurons expressing human Aβ and exposed to human ApoE4 over nine days in culture. Result: A primary screen of two small molecule libraries identified 31 hit compounds that significantly inhibited ApoE4‐catalyzed Aβ fibrillization in a dose‐dependent manner. Primary hit compounds were then tested in primary mouse neurons, where six compounds were validated as non‐cytotoxic and were effective at inhibiting Aβ neuropathology. One of the six lead compounds (epigallocatechin gallate) had been studied previously as a potential therapy for neurodegenerative disease, thus validating the overall screening approach. Conclusion: Six small molecule compounds were identified as novel inhibitors of ApoE4‐catalyzed Aβ fibrillization in high‐throughput screens. Three are FDA‐approved drugs for indications unrelated to AD. We are currently performing preclinical evaluations of these compounds in AD rodent models to determine their therapeutic potential for the treatment of AD.