O3-02-05: p21-activated kinase pathway defects and synaptic function in Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is characterized by cognitive deficits. These may stem from a selective attack of soluble beta amyloid peptide aggregates (Aβ) on a p21 activated kinase (PAK) pathway that plays a critical role in excitatory synapse formation and function involved in learning and memory. Normal excitatory synapse formation and function requires precise synaptic PAK1 and PAK3 localization in protein complexes coupled to synaptic receptors via appropriate adaptor proteins including PIX and GIT1 to signal through LIMK1 to cofilin and the actin cytoskeleton and to the ERK> CREB pathway for synaptic plasticity/ LTP. We have reported defects in PAK kinases and excitatory synapse markers, notably drebrin, in AD, transgenic mice, and in vitro model systems with elevated soluble Aβ oligomers. Protection was afforded by passive anti–Aβ antibody in vivo or in vitro or PAK over–expression. We investigated whether aberrant activation of PAKs is associated with translocation of both PAK and PIX to membrane receptors with another adaptor protein, Nck, which couples the PAK complex to JNK and a cascade involved in neurodegeneration. Immunoprecipitation, Western blot and Immunohistochemistry methods were used on AD tissue and model systems. We found Nck, PAK and PIX translocation to the membrane in AD. Nck translocation is highly correlated with loss of soluble PAK, notably PAK3, and predicted to lead to reduced ERK>CREB and increased JNK signaling. In vitro, Aβ oligomers resulted in rapid translocation of active PAK and PIX followed by a loss of active PAK. This was partially protected by the anti–oligomer agent curcumin or by inhibition of either calpain or a known Aβ effector, Cdk5, which is chronically activated in AD. PAK association with Nck and aberrant translocation to membrane and rac1 activation can also be directly suppressed by neurotrophic or insulin signaling through the PI3–K> Akt pathway which inhibits rac1 and phosphorylates PAK at its Nck binding site, dissociating PAK from Nck and ectopic membrane complexes. This model explains how dietary agents like curcumin and the omega 3 fatty acid DHA that promotes Akt activation may protect against synaptic signaling defects induced by Aβ in AD.