Identification of tetrahydrocarbazoles as novel multifactorial drug candidates for treatment of Alzheimer’s disease

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...

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Bibliographic Details
Published in:	Translational psychiatry Vol. 4; no. 12; p. e489
Main Authors:	Honarnejad, K, Daschner, A, Gehring, A P, Szybinska, A, Giese, A, Kuznicki, J, Bracher, F, Herms, J
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 16-12-2014 Nature Publishing Group
Subjects:	13 14 14/33 14/56 14/63 631/154/436 Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Amyloid beta-Peptides - drug effects Amyloid beta-Peptides - metabolism Behavioral Sciences Biological Psychology Calcium - metabolism Carbazoles - pharmacology Drug Discovery - methods Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - metabolism HEK293 Cells Homeostasis - drug effects Homeostasis - physiology Humans Medicine Medicine & Public Health Mitochondria - drug effects Mitochondria - metabolism Neurosciences Original original-article Pharmacotherapy Psychiatry
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany.
ISSN:	2158-3188 2158-3188
DOI:	10.1038/tp.2014.132