title: The multi-functional drug tropisetron binds APP and normalizes cognition in a murine Alzheimer's model.
abstract: Tropisetron was identified in a screen for candidates that increase the ratio of the trophic, neurite-extending peptide sAPPα to the anti-trophic, neurite-retractive peptide Aβ, thus reversing this imbalance in Alzheimer's disease (AD). We describe here a hierarchical screening approach to identify such drug candidates, moving from cell lines to primary mouse hippocampal neuronal cultures to in vivo studies. By screening a clinical compound library in the primary assay using CHO-7W cells stably transfected with human APPwt, we identified tropisetron as a candidate that consistently increased sAPPα. Secondary assay testing in neuronal cultures from J20 (PDAPP, huAPP(Swe/Ind)) mice showed that tropisetron consistently increased the sAPPα/Aβ 1-42 ratio. In in vivo studies in J20 mice, tropisetron improved the sAPPα/Aβ ratio along with spatial and working memory in mice, and was effective both during the symptomatic, pre-plaque phase (5-6 months) and in the late plaque phase (14 months). This ameliorative effect occurred at a dose of 0.5mg/kg/d (mkd), translating to a human-equivalent dose of 5mg/day, the current dose for treatment of postoperative nausea and vomiting (PONV). Although tropisetron is a 5-HT3 receptor antagonist and an α7nAChR partial agonist, we found that it also binds to the ectodomain of APP. Direct comparison of tropisetron to the current AD therapeutics memantine (Namenda) and donepezil (Aricept), using similar doses for each, revealed that tropisetron induced greater improvements in memory and the sAPPα/Aβ1-42 ratio. The improvements observed with tropisetron in the J20 AD mouse model, and its known safety profile, suggest that it may be suitable for transition to human trials as a candidate therapeutic for mild cognitive impairment (MCI) and AD, and therefore it has been approved for testing in clinical trials beginning in 2014.
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Spilman
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Descamps
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Gorostiza
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Clare
authors.initials: C
authors.lastname: Peters-Libeu
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Poksay
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Matalis
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Campagna
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Patent
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Rammohan
authors.initials: R
authors.lastname: Rao
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA; Dominican University of California, San Rafael, CA 94901, USA.
authors.forename: Varghese
authors.initials: V
authors.lastname: John
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA; Department of Neurology, University of California, San Francisco, CA 94143, USA. Electronic address: dbredesen@buckinstitute.org.
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D003071:Cognition / Q000187:drug effects*; D003412:Cricetulus; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D000077526:Tropisetron
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007211:Indoles; D000077526:Tropisetron
keywords: Alzheimer's disease; Candidate therapeutic; Improvement in sAPPα/Aβ42 biomarker ratio; Memory improvement; Multi-functional drug; Orally effective