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.

journal_name

Exp Gerontol

journal_title

Experimental gerontology

authors

Dedeoglu A,Cormier K,Payton S,Tseitlin KA,Kremsky JN,Lai L,Li X,Moir RD,Tanzi RE,Bush AI,Kowall NW,Rogers JT,Huang X

doi

10.1016/j.exger.2004.08.016

keywords:

subject

Has Abstract

pub_date

2004-11-01 00:00:00

pages

1641-9

issue

11-12

eissn

0531-5565

issn

1873-6815

pii

S0531-5565(04)00279-7

journal_volume

39

pub_type

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