Background: Defects of p21-activated kinase (PAK) lead to dendritic spines abnormalities and cognitive impairment, and have thus been hypothesized to play a role in Alzheimer's disease (AD). Methods:Western immunoblots, Elisa, electrophysiology and behavior assessment. Results:We first quantified PAK by immunoblotting in homogenates from the parietal neocortex of subjects with a clinical diagnosis of AD (n = 12), MCI (Mild cognitive impairment, n =12) or no cognitive impairment (NCI, n=12). A loss of PAK was detected in the cortex of AD patients (-39 % versus controls), but not of its phosphorylated form, and was correlated with cognitive impairment (r2=0.148 P=0.027) and deposition of total and phosphorylated tau (r2 = 0.235 and r2 = 0.206 respectively), but not with Ab42 (r2 = 0.056). Accordingly, we found a decrease of cofilin and PAK, but not of its phosphorylated form, in the cortex of 12 and 18-months-old 3xTg-AD mice, suggesting that the PAK dysfunction occurring in AD can be replicated in this animal model of AD-like Ab and tau neuropathologies. To probe the causal role of PAK, we crossed 3xTg-AD mice with dominantnegative PAK (dnPAK) mice. Behavioral assessments revealed that 3xTg- ADxdnPAK mice exhibited anxious traits and pronounced disturbances in social recognition and interaction compared to 3xTg-AD mice. Morphometric analyses of layer II/III showed significant dendritic attrition, reduced spine density and spine lengthening in 3xTg-ADxdnPAKpyramidal neurons from the frontal cortex compared to NonTg and 3xTg-AD mice. Whole-cell patch clamp recordings indicated that PAK inactivation blunted change in glutamatergic activity in frontal cortex neurons, while decreasing the firing rate and increasing mIPSC of entorhinal cortex neurons from 3xTg-AD mice. Surprisingly, the expression of dnPAK reduced the deposition of Ab and tau in detergent-insoluble fractions from the parieto-temporal cortex, whereas this effect was limited to tau in the frontal cortex. Conclusions: In summary, our results revealed a complex region-dependent impact of PAKon ADneuropathology and neuronal function, but nonetheless substantiate a critical role for PAK in the genesis of neuronal abnormalities underlying the emergence of symptoms in AD.
Arsenault, D., Cyril, B., Tremblay, C., Dal-Pan, A., Bennett, D., Tonegawa, S., … Calon, F. (2012). O5-01-02: Defects in p21-activated kinase (PAK) in Alzheimer’s disease: A causal role? Alzheimer’s & Dementia, 8(4S_Part_20), P729–P730. https://doi.org/10.1016/j.jalz.2012.05.1970