title: Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer's disease models.
abstract: Alzheimer's disease (AD) is characterized by synaptic and neuronal loss, which occurs at least partially through oxidative stress induced by oligomeric amyloid-β (Aβ)-peptide. Carnosic acid (CA), a chemical found in rosemary and sage, is a pro-electrophilic compound that is converted to its active form by oxidative stress. The active form stimulates the Keap1/Nrf2 transcriptional pathway and thus production of phase 2 antioxidant enzymes. We used both in vitro and in vivo models. For in vitro studies, we evaluated protective effects of CA on primary neurons exposed to oligomeric Aβ. For in vivo studies, we used two transgenic mouse models of AD, human amyloid precursor protein (hAPP)-J20 mice and triple transgenic (3xTg AD) mice. We treated these mice trans-nasally with CA twice weekly for 3 months. Subsequently, we performed neurobehavioral tests and quantitative immunohistochemistry to assess effects on AD-related phenotypes, including learning and memory, and synaptic damage. In vitro, CA reduced dendritic spine loss in rat neurons exposed to oligomeric Aβ. In vivo, CA treatment of hAPP-J20 mice improved learning and memory in the Morris water maze test. Histologically, CA increased dendritic and synaptic markers, and decreased astrogliosis, Aβ plaque number, and phospho-tau staining in the hippocampus. We conclude that CA exhibits therapeutic benefits in rodent AD models and since the FDA has placed CA on the 'generally regarded as safe' (GRAS) list, thus obviating the need for safety studies, human clinical trials will be greatly expedited.
authors.affiliation: Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA.|Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.|Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Tayebeh
authors.initials: T
authors.lastname: Rezaie
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nutter
authors.affiliation: Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA.|Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Lopez
authors.affiliation: Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA.|Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: James
authors.identifier: 0000-0002-1150-8374
authors.initials: J
authors.lastname: Parker
authors.affiliation: Research and Development Center, Nagase CO., LTD., Kobe, Hyogo 651-2241, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Kosaka
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Takumi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA.|Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.affiliation: Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA.|Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
mesh_terms: D045784:Abietanes / Q000494:pharmacology / Q000627:therapeutic use*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008822:Mice, Transgenic; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D065853:Spatial Learning / Q000187:drug effects; D013194:Staining and Labeling; D013569:Synapses / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D045784:Abietanes; D016229:Amyloid beta-Peptides; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D051267:NF-E2-Related Factor 2; D016708:Synaptophysin; C018381:salvin