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Article type: Research Article
Authors: Gourmaud, Saraha; 1 | Mouton-Liger, Françoisb | Abadie, Clairec | Meurs, Eliane F.d | Paquet, Clairea; e | Hugon, Jacquesa; e; *
Affiliations: [a] Inserm UMR-S 942, Paris, France | [b] Brain and Spine Institute, Paris, France | [c] Solid Drug Development, Geneva, Switzerland | [d] Institut Pasteur, Hepacivirus and Innate Immunity Unit, Paris, France | [e] Research Memory Centre, Paris Nord Ile de France Saint Louis Lariboisière Fernand Widal Hospital, Paris, France
Correspondence: [*] Correspondence to: Jacques Hugon, 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].
Note: [1] Current address: Perelman School of Medicine, University of Pennsylvania, Department of Neurology, Philadelphia, PA, USA.
Abstract: In Alzheimer’s disease (AD), the amyloid cascade hypothesis proposes that amyloid-beta (Aβ) neurotoxicity leads to neuroinflammation, synaptic loss, and neuronal degeneration. In AD patients, anti-amyloid immunotherapies did not succeed because they were possibly administered late in AD progression. Modulating new targets associated with Aβ toxicity, such as PKR (double-stranded RNA dependent kinase), and JNK (c-Jun N-terminal kinase) is a major goal for neuroprotection. These two pro-apoptotic kinases are activated in AD brains and involved in Aβ production, tau phosphorylation, neuroinflammation, and neuronal death. In HEK cells transfected with siRNA directed against PKR, and in PKR knockout (PKR–/–) mice neurons, we showed that PKR triggers JNK activation. Aβ-induced neuronal apoptosis, measured by cleaved PARP (Poly ADP-ribose polymerase) and cleaved caspase 3 levels, was reduced in PKR–/– neurons. Two selective JNK inhibitory peptides also produced a striking reduction of Aβ toxicity. Finally, the dual inhibition of PKR and JNK nearly abolished Aβ toxicity in primary cultured neurons. These results reveal that dual kinase inhibition can afford neuroprotection and this approach is worth being tested in in vivo AD and oxidative stress models.
Keywords: Alzheimer’s disease, amyloid-beta, JNK, neuronal death, PKR, therapeutic strategy
DOI: 10.3233/JAD-160509
Journal: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1659-1670, 2016
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