Research Paper Volume 9, Issue 5 pp 1386—1403

Transgenic autoinhibition of p21-activated kinase exacerbates synaptic impairments and fronto-dependent behavioral deficits in an animal model of Alzheimer’s disease

Cyril Bories1, , Dany Arsenault2,3, , Myriam Lemire1, , Cyntia Tremblay2,3, , Yves De Koninck1, , Frédéric Calon2,3, ,

  • 1 Research Center of Institut Universitaire en Santé Mentale de Québec, Quebec City, QC, Canada
  • 2 Faculty of Pharmacy Laval University, Quebec City, QC, Canada
  • 3 Centre Hospitalier de l'Université Laval (CHUL) Research Center, Quebec City, QC, Canada
* Equal contribution

Received: January 23, 2017       Accepted: May 11, 2017       Published: May 16, 2017
How to Cite

Copyright: © 2017 Bories et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Defects in p21-activated kinase (PAK) lead to dendritic spine abnormalities and are sufficient to cause cognition impairment. The decrease in PAK in the brain of Alzheimer's disease (AD) patients is suspected to underlie synaptic and dendritic disturbances associated with its clinical expression, particularly with symptoms related to frontal cortex dysfunction. To investigate the role of PAK combined with Aβ and tau pathologies (3xTg-AD mice) in the frontal cortex, we generated a transgenic model of AD with a deficit in PAK activity (3xTg-AD-dnPAK mice). PAK inactivation had no effect on Aβ40 and Aβ42 levels, but increased the phosphorylation ratio of tau in detergent-insoluble protein fractions in the frontal cortex of 18-month-old heterozygous 3xTg-AD mice. Morphometric analyses of layer II/III pyramidal neurons in the frontal cortex showed that 3xTg-AD-dnPAK neurons exhibited significant dendritic attrition, lower spine density and longer spines compared to NonTg and 3xTg-AD mice. Finally, behavioral assessments revealed that 3xTg-AD-dnPAK mice exhibited pronounced anxious traits and disturbances in social behaviors, reminiscent of fronto-dependent symptoms observed in AD. Our results substantiate a critical role for PAK in the genesis of neuronal abnormalities in the frontal cortex underlying the emergence of psychiatric-like symptoms in AD.


3xTg-AD: triple transgenic mouse model of Alzheimer’s disease; Aβ: abeta peptide; AD: Alzheimer disease; AMPA: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Cdk5: Cyclin-dependent kinase 5; dnPAK: dominant negative PAK; EPSCs: excitatory postsynaptic currents; GABA: gamma-aminobutyric acid; GAD65: glutamic acid decarboxylase 65 KDa; GluN2B: NMDA receptor GluN2B (GluR epsilon 2/NR2B) subunit; GSK3: glycogen synthase kinase 3; mEPSCs: miniature excitatory postsynaptic currents; mPSCs: miniature postsynaptic currents; NonTg: non-transgenic; PAK: p21-activated kinase; pPAK: phosphorylated PAK; PSCs: postsynaptic currents; PSD95: postsynaptic density protein 95; Ser: serine; Thr: threonine; TTX: tetradotoxin; VGAT: vesicular GABA transporter.