New piperazine multi-effect drugs prevent neurofibrillary degeneration and amyloid deposition, and preserve memory in animal models of Alzheimer's disease

NEUROBIOLOGY OF DISEASE

卷:129

Article

Sergeant, Nicolas¹  Vingtdeux, Valerie¹  Eddarkaoui, Sabiha¹  Gay, Marion¹  Evrard, Caroline¹  Le Fur, Nicolas¹  Laurent, Cyril¹  Caillierez, Raphaelle¹  Obriot, Helene¹  Larchanche, Paul-Emmanuel¹  Farce, Amaury²  Coevoet, Mathilde¹  Carato, Pascal^1,5  Kouach, Mostafa³  Descat, Amandine³  Dallemagne, Patrick⁴  Buee-Scherrer, Valerie¹  Blum, David¹  Hamdane, Malika¹  Buee, Luc¹  Melnyk, Patricia¹ 

[1] Univ Lille, INSERM, CHU Lille, UMR S1172,JPArc,Ctr Rech Jean Pierre Aubert Neuro, F-59000 Lille, France

[2] Univ Lille, INSERM, U995, CHU Lille,LIRIC, F-59000 Lille, France

[3] Univ Lille, CUMA, F-59000 Lille, France

[4] UNICAEN, UFR Sci Pharmaceut, EA 4258, CERMN, F-14032 Caen, France

[5] Univ Poitiers, CNRS, UMR 7285, IC2MP, F-86073 Poitiers, France

关键词: Alzheimer's disease;    Amyloid;    Microtubule-associated protein tau;    Multi-effect drugs;    Neurofibrillary tangles;    Tauopathies;    Acetylcholinesterase;   

DOI  :  10.1016/j.nbd.2019.03.028

来源: Elsevier

【 摘 要 】

Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi effects compounds by synthesizing drug candidates derived by substituting a novel N,N'-disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property. Two compounds were synthesized and evaluated. The most promising hybrid molecule reduces both the amyloid pathology and the Tau pathology as well as the memory impairments in a preclinical model of Alzheimer's disease. In vitro also, the compound reduces the phosphorylation of Tau and inhibits the release of A beta peptides while preserving the processing of other metabolites of the amyloid precursor protein. We synthetized and tested the first drug capable of ameliorating both the amyloid and Tau pathology in animal models of AD as well as preventing the major brain lesions and associated memory impairments. This work paves the way for future compound medicines against both Alzheimer's-related brain lesions development and the associated cognitive impairments.

【 授权许可】

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