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978-3-8439-1713-1, Reihe Neurowissenschaften
Discovery and characterization of novel drugs for treatment of Alzheimer disease from a high-throughput compound screen
173 Seiten, Dissertation Ludwig-Maximilians-Universität München (2014), Softcover, A5
Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most frequent cause of dementia. To date, there are few approved symptomatic drugs for treatment of AD, which show little or no effect on disease progression.
Within this work we characterized the role of presenilin mutations in AD-associated impairment of endoplasmic reticulum (ER) calcium homeostasis. Based on those findings, we examined the possibility of pharmacologically reversing the disrupted calcium homeostasis in the ER as an innovative approach for AD drug discovery. Therefore, we developed a fully automated high-throughput calcium imaging assay utilizing a genetically-encoded calcium sensor and subsequently screened a large collection of compounds. High-throughput drug screening led to the identification of a number of novel drug candidates that were characterized and validated for their relevance in AD therapy using a number of secondary assays.
We performed a truly high-throughput compound screen with a diverse library of 20,000 small molecules, which resulted in identification of five novel lead structures. Amongst them were tetrahydrocarbazoles, a novel multifactorial class of compounds that can reverse the impaired ER calcium homeostasis. We found that tetrahydrocarbazole lead structure, firstly, dampens the potentiated calcium release from ER in HEK293 cells expressing FAD-PS1 mutations. Secondly, the lead structure also improves mitochondrial function, measured by increased mitochondrial membrane potential. Thirdly, the same lead structure also attenuates the production of Aβ peptides by decreasing the cleavage of Amyloid Precursor Protein (APP) by β-secretase, without notably affecting α- and γ-secretase cleavage activities. Considering tetrahydrocarbazoles’ multiple modes of action by addressing three key pathological aspects of AD, this compound class holds promise for development of a potentially effective AD drug candidate.