title: Dual Kinase Inhibition Affords Extended in vitro Neuroprotection in Amyloid-β Toxicity.
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.
authors.affiliation: Inserm UMR-S 942, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gourmaud
authors.affiliation: Brain and Spine Institute, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Mouton-Liger
authors.affiliation: Solid Drug Development, Geneva, Switzerland.
authors.forename: Claire
authors.initials: C
authors.lastname: Abadie
authors.affiliation: Institut Pasteur, Hepacivirus and Innate Immunity Unit, Paris, France.
authors.forename: Eliane F
authors.initials: EF
authors.lastname: Meurs
authors.affiliation: Inserm UMR-S 942, Paris, France.|Research Memory Centre, Paris Nord Ile de France Saint Louis Lariboisière Fernand Widal Hospital, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Paquet
authors.affiliation: Inserm UMR-S 942, Paris, France.|Research Memory Centre, Paris Nord Ile de France Saint Louis Lariboisière Fernand Widal Hospital, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Hugon
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D000066829:Neuroprotection / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D047428:Protein Kinase Inhibitors
keywords: Alzheimer’s disease; JNK; PKR; amyloid-beta; neuronal death; therapeutic strategy