title: Identification of tetrahydrocarbazoles as novel multifactorial drug candidates for treatment of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most frequent cause of dementia. To date, there are only a few approved drugs for AD, which show little or no effect on disease progression. Impaired intracellular calcium homeostasis is believed to occur early in the cascade of events leading to AD. Here, we examined the possibility of normalizing the disrupted calcium homeostasis in the endoplasmic reticulum (ER) store as an innovative approach for AD drug discovery. High-throughput screening of a small-molecule compound library led to the identification of tetrahydrocarbazoles, a novel multifactorial class of compounds that can normalize the impaired ER calcium homeostasis. We found that the tetrahydrocarbazole lead structure, first, dampens the enhanced calcium release from ER in HEK293 cells expressing familial Alzheimer's disease (FAD)-linked presenilin 1 mutations. Second, the lead structure also improves mitochondrial function, measured by increased mitochondrial membrane potential. Third, the same lead structure also attenuates the production of amyloid-beta (Aβ) peptides by decreasing the cleavage of amyloid precursor protein (APP) by β-secretase, without notably affecting α- and γ-secretase cleavage activities. Considering the beneficial effects of tetrahydrocarbazoles addressing three key pathological aspects of AD, these compounds hold promise for the development of potentially effective AD drug candidates.
authors.affiliation: 1] Department of Translational Brain Research, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany [2] Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany [3] Graduate School of Systemic Neurosciences, Ludwig Maximilian University, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Honarnejad
authors.affiliation: 1] Department of Translational Brain Research, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany [2] Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Daschner
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwig Maximilian University, Munich, Germany.
authors.forename: A P
authors.initials: AP
authors.lastname: Gehring
authors.affiliation: Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Szybinska
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Giese
authors.affiliation: Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Kuznicki
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwig Maximilian University, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Bracher
authors.affiliation: 1] Department of Translational Brain Research, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany [2] Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany [3] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Herms
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002227:Carbazoles; D002118:Calcium