Affiliations: [a] Inserm UMR-S 942, Paris, France
| [b] Solid Drug Development, Geneva, Switzerland
| [c]
Research Memory Centre, Paris Nord Ile de France Saint Louis Lariboisière Fernand Widal Hospital, University Paris Diderot AP-HP, Paris, France
| [d] Present address: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Correspondence:
[*]
Correspondence to: Jacques Hugon, Inserm UMR-S942 and Memory Clinical Centre Paris Nord Ile-de-France, 200 rue du Faubourg Saint-Denis, 75010 Paris, France. Tel.: +33 1 45 87 61 55; Fax: +33 1 45 87 61 32; E-mail: [email protected].
Abstract: Alzheimer’s disease (AD) is characterized by accumulations of amyloid-β (Aβ42) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8). Three-month-old 5XFAD and wild-type littermate mice were treated by intravenous injections of low doses (10 mg/kg) of Brimapitide every 3 weeks, for 3 or 6 months (n = 6–9 per group). Cognitive deficits and brain lesions were assessed using Y-maze, fear-conditioning test, and histological and biochemical methods. Chronic treatment of Brimapitide for 3 months resulted in a reduction of Aβ plaque burden in the cortex of 5XFAD treated mice. After 6 months of treatment, cognitive deficits were reduced but also a significant reduction of cell death markers and the pro-inflammatory IL-1β cytokine in treated mice were detected. The Aβ plaque burden was not anymore modified by the 6 months of treatment. In addition to modulating cognition and amyloid plaque accumulation, depending on the treatment duration, Brimapitide seems experimentally to reduce neuronal stress in 5XFAD mice.
