title: A derivative of the brain metabolite lanthionine ketimine improves cognition and diminishes pathology in the 3 × Tg-AD mouse model of Alzheimer disease.
abstract: Lanthionine ketimine ([LK] 3,4-dihydro-2H-1,4-thiazine-3,5-dicarboxylic acid) is the archetype for a family of naturally occurring brain sulfur amino acid metabolites, the physiologic function of which is unknown. Lanthionine ketimine and its synthetic derivatives have recently demonstrated neurotrophic, neuroprotective, and antineuroinflammatory properties in vitro through a proposed mechanism involving the microtubule-associated protein collapsin response mediator protein 2. Therefore, studies were undertaken to test the effects of a bioavailable LK ester in the 3 × Tg-AD mouse model of Alzheimer disease. Lanthionine ketimine ester treatment substantially diminished cognitive decline and brain amyloid-β (Aβ) peptide deposition and phospho-Tau accumulation in 3 × Tg-AD mice and also reduced the density of Iba1-positive microglia. Furthermore, LK ester treatment altered collapsin response mediator protein 2 phosphorylation. These findings suggest that LK may not be a metabolic waste but rather a purposeful neurochemical, the synthetic derivatives of which constitute a new class of experimental therapeutics for Alzheimer disease and related entities.
authors.affiliation: From the Departments of Pathology (KH, KV, AH) and Neurosciences (KH), University of Toledo Medical Center, Toledo; and P2D Bioscience, Inc., Cincinnati (SPG), Ohio; and Veterans Administration-Greater Los Angeles Healthcare System and David Geffen School of Medicine at the University of California, Los Angeles, California (MFJ, PE, MEH-W).
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hensley
authors.forename: S Prasad
authors.initials: SP
authors.lastname: Gabbita
authors.forename: Kalina
authors.initials: K
authors.lastname: Venkova
authors.forename: Alexandar
authors.initials: A
authors.lastname: Hristov
authors.forename: Ming F
authors.initials: MF
authors.lastname: Johnson
authors.forename: Pirooz
authors.initials: P
authors.lastname: Eslami
authors.forename: Marni E
authors.initials: ME
authors.lastname: Harris-White
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000603:Amino Acids, Sulfur / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D045744:Cell Line, Tumor; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009425:Nesting Behavior / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D000603:Amino Acids, Sulfur; C035499:lanthionine ketimine