title: Reduced Alzheimer's disease pathology by St. John's Wort treatment is independent of hyperforin and facilitated by ABCC1 and microglia activation in mice.
abstract: Soluble β-amyloid peptides (Aβ) and small Aβ oligomers represent the most toxic peptide moieties recognized in brains affected by Alzheimer's disease (AD). Here we provide the first evidence that specific St. John's wort (SJW) extracts both attenuate Aβ-induced histopathology and alleviate memory impairments in APP-transgenic mice. Importantly, these effects are attained independently of hyperforin. Specifically, two extracts characterized by low hyperforin content (i) significantly decrease intracerebral Aβ42 levels, (ii) decrease the number and size of amyloid plaques, (iii) rescue neocortical neurons, (iv) restore cognition to normal levels, and (iv) activate microglia in vitro and in vivo. Mechanistically, we reveal that the reduction of soluble Aβ42 species is the consequence of a highly increased export activity in the bloodbrain barrier ABCC1transporter, which was found to play a fundamental role in Aβ excretion into the bloodstream. These data (i) support the significant beneficial potential of SJW extracts on AD proteopathy, and (ii) demonstrate for the first time that hyperforin concentration does not necessarily correlate with their therapeutic effects. Hence, by activating ABC transporters, specific extracts of SJW may be used to treat AD and other diseases involving peptide accumulation and cognition impairment. We propose that the anti-depressant and anti-dementia effects of these hyperforin-reduced phytoextracts could be combined for treatment of the elderly, with a concomitant reduction in deleterious hyperforin-related side effects.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hofrichter
authors.forename: Markus
authors.initials: M
authors.lastname: Krohn
authors.forename: Toni
authors.initials: T
authors.lastname: Schumacher
authors.forename: Cathleen
authors.initials: C
authors.lastname: Lange
authors.forename: Björn
authors.initials: B
authors.lastname: Feistel
authors.forename: Bernd
authors.initials: B
authors.lastname: Walbroel
authors.forename: Hans-Jochen
authors.initials: HJ
authors.lastname: Heinze
authors.forename: Sara
authors.initials: S
authors.lastname: Crockett
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Sharbel
authors.affiliation: University of Magdeburg, Department of Neurology, Neurodegeneration Research Laboratory (NRL), Leipziger Str. 44, Bldg 64, 39120 Magdeburg, Germany. jens.pahnke@web.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D020902:Hypericum / Q000737:chemistry*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010586:Phagocytes / Q000187:drug effects; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000627:therapeutic use; D008517:Phytotherapy; D028321:Plant Preparations / Q000737:chemistry / Q000627:therapeutic use*; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000209:etiology; D013729:Terpenes / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010446:Peptide Fragments; D010696:Phloroglucinol; D028321:Plant Preparations; D013729:Terpenes; C075222:amyloid beta-protein (1-42); C001654:hyperforin; C421109:multidrug resistance-associated protein 1