N′-Benzylidene-Benzohydrazides as Novel and Selective Tau-PHF Ligands

Article type: Research Article

Authors: Taghavi, Ali^a | Nasir, Samir^a | Pickhardt, Marcus^b | Hauβen, Roland Heyny-von^c | Mall, Gerhard^c | Mandelkow, Eckhard^b | Mandelkow, Eva-Maria^b | Schmidt, Boris^{a; *}

Affiliations: [a] Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universtität Darmstadt, Darmstadt, Germany | [b] Max-Planck-Unit for Structural Molecular Biology, c/o DESY, Hamburg, Germany | [c] Department of Pathology, Klinikum Darmstadt, Darmstadt, Germany

Correspondence: [*] Correspondence to: Prof. Dr. Boris Schmidt, Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany. Tel.: (+49) 6151 163075; Fax: (+49) 6151 163278; E-mail: [email protected].

Abstract: The structure activity relationship of N′-benzylidene-benzohydrazide (NBB) binding to tau and paired helical filament (PHF) proteins as well as amyloid-β1-42 fibrils indicate differential selectivity for these protein aggregates. The ability of the compounds to stain neurofibrillary tangles and senile plaques isolated from human AD brain was investigated histochemically. These studies resulted in several tau-PHF and amyloid-β1-42 fibril selective ligands respectively. Supported by these results, we rationalized a model for the design of selective ligands for tau, PHF, and amyloid-β1-42 fibrils.

Keywords: Alzheimer's disease, amyloid-β, amphiphilicity, amphiphilic ligands, N′-benzylidene-benzohydrazide, neurofibrillary tangle, paired helical filament, selective tau ligands, tau, tau and PHF proteins

DOI: 10.3233/JAD-2011-111238

Journal: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 835-843, 2011