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

Nicolas Sergeant 1 Valérie Vingtdeux 1 Sabiha Eddarkaoui 1 Marion Gay 1 Caroline Evrard 1 Nicolas Le Fur 1 Cyril Laurent 1 Raphaëlle Caillierez 1 Hélène Obriot 1 Paul-Emmanuel Larchanché 1 Amaury Farce 2 Mathilde Coevoet 1 Pascal Carato 1 Mostafa Kouach 3 Amandine Descat 3 Patrick Dallemagne 4 Valérie Buée-Scherrer 1 David Blum 1 Malika Hamdane 1 Luc Buee 1, * Patricia Melnyk 1, *
* Corresponding author
1 JPArc - U1172 Inserm - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer
2 LIRIC - Lille Inflammation Research International Center
3 CUMA - Centre Universitaire de Mesures et d'Analyses [UNIV Lille]
4 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
Abstract : 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 Aβ 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.
Keywords : Acetylcholinesterase Alzheimer's disease Amyloid Microtubule-associated protein tau Multi-effect drugs Neurofibrillary tangles Tauopathies
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Nicolas Sergeant, Valérie Vingtdeux, Sabiha Eddarkaoui, Marion Gay, Caroline Evrard, et al.. New piperazine multi-effect drugs prevent neurofibrillary degeneration and amyloid deposition, and preserve memory in animal models of Alzheimer's disease. Neurobiology of Disease, Elsevier, 2019, 129, pp.217-233. ⟨10.1016/j.nbd.2019.03.028⟩. ⟨inserm-02350071⟩

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