Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis.
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.
Dedeoglu
Alpaslan
A
Geriatric Research Education and Clinical Center, Bedford Veterans' Administration Medical Center, Bedford, MA 01730, USA.
Cormier
Kerry
K
Payton
Sandra
S
Tseitlin
Katya A
KA
Kremsky
Jonathan N
JN
Lai
Li
L
Li
Xiaohua
X
Moir
Robert D
RD
Tanzi
Rudolph E
RE
Bush
Ashley I
AI
Kowall
Neil W
NW
Rogers
Jack T
JT
Huang
Xudong
X
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
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002614:Chelating Agents; D008670:Metals; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)