title: Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis.
abstract: A growing body of evidence indicates that dysregulation of cerebral biometals (Fe, Cu, Zn) and their interactions with APP and Abeta amyloid may contribute to the Alzheimer's amyloid pathology, and thus metal chelation could be a rational therapeutic approach for interdicting AD pathogenesis. However, poor target specificity and consequential clinical safety of current metal-complexing agents have limited their widespread clinical use. To develop the next generation of metal chelators, we have designed and synthesized a new bifunctional molecule-XH1, based on a novel 'pharmacophore conjugation' concept. This lipophilic molecule has both amyloid-binding and metal-chelating moieties covalently connected by amide bonds. It achieved a putative binding geometry with Abeta1-40 peptide by the computational chemistry modeling and reduced Zn(II)-induced Abeta1-40 aggregation in vitro as determined by turbidometry. Moreover, our pilot data indicated that XH1 has no significant neurotoxicity at low micromolar concentrations and acute animal toxicity. XH1 specifically reduced APP protein expression in human SH-SY5Y neuroblastoma cells and attenuated cerebral Abeta amyloid pathology in PS1/APP transgenic mice without inducing apparent toxicity and behavior disturbances. Collectively, these preliminary findings carry implication for XH1 being a BBB-permeable lead compound for AD therapeutics targeting Alzheimer's amyloidogenesis, although further studies are needed.
authors.affiliation: Geriatric Research Education and Clinical Center, Bedford Veterans' Administration Medical Center, Bedford, MA 01730, USA.
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Dedeoglu
authors.forename: Kerry
authors.initials: K
authors.lastname: Cormier
authors.forename: Sandra
authors.initials: S
authors.lastname: Payton
authors.forename: Katya A
authors.initials: KA
authors.lastname: Tseitlin
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Kremsky
authors.forename: Li
authors.initials: L
authors.lastname: Lai
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Robert D
authors.initials: RD
authors.lastname: Moir
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.forename: Neil W
authors.initials: NW
authors.lastname: Kowall
authors.forename: Jack T
authors.initials: JT
authors.lastname: Rogers
authors.forename: Xudong
authors.initials: X
authors.lastname: Huang
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D001932:Brain Neoplasms; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008670:Metals; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002614:Chelating Agents; D008670:Metals; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)