Dual Kinase Inhibition Affords Extended in vitro Neuroprotection in Amyloid-β Toxicity

In Alzheimer's disease (AD), the amyloid cascade hypothesis proposes that amyloid-beta (A beta) 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 A beta 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 A beta 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. A beta-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 A beta toxicity. Finally, the dual inhibition of PKR and JNK nearly abolished A beta 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.