Neurochemistry DOI.docVIP

Ne 神经化学DOINeurochemistry DOI.uro DOI: 10.1002/anie.201209885 Development of a Platinum Complex as an anti-Amyloid Agent for the Therapy of Alzheimer_s Disease 铂复杂的发展作为一个种抗体代理Alzheimer_s疾病的治疗 Vijaya B. Kenche, Lin W. Hung, Keyla Perez, Irene Volitakes, Guiseppe Ciccotosto,Jeffrey Kwok, Nicole Critch, Nikki Sherratt, Mikhalina Cortes, Varsha Lal, Colin L. Masters,Kazuma Murakami, Roberto Cappai, Paul A. Adlard, and Kevin J. Barnham* 林Vijaya b . Kenche w .挂Keyla佩雷斯,Irene Volitakes Guiseppe Ciccotosto,妮可不久后,尼基中,杰弗里·郭Mikhalina议会,Varsha Lal,科林·l·大师Kazuma村上,Roberto Cappai Paul a .埃德拉德合作,凯文·j·Barnham * Alzheimer_s disease (AD) is an age-related neurodegenerative disease. Its pathological indicators include extracellular amyloid plaques, the main constituent of which is the amyloid b-peptide (Ab), and neurofibrillary tangles composed of hyperphosphorylated tau protein.[1] Current evidence suggests that the aggregation of Abs drives the disease process, as various forms of aggregated Ab have been shown to be toxic,[2] resulting in the development of a variety of therapeutic strategies that target Ab.[3?6] To date, most Ab aggregation inhibitors have been designed to target the hydrophobic central and C-terminal regions of Ab, which are in general conjugated polyaromatic molecules that are very hydrophobic.[7] Herein, we report a different approach to the design of aggregation inhibitors of Ab and demonstrate that this approach can modify Ab in vivo. Ab contains a metalbinding motif with three histidine residues (6, 13, and 14) near the N terminus, and the interaction of this site with zinc and copper modulates the aggregation and toxicity of Ab.[8,9] We have previously taken advantage of the metal-binding ability of Ab to show that commercially available PtII complexes of 1,10-phenanthroline ligands target this site, thus inhibiting Ab aggregation in vitro.[10] For a variety of reasons, including lack of novelty, cumbersome multi-s