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

Aging
Cyril BoriesFrederic Calon

Abstract

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 ...Continue Reading

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Citations

Jun 14, 2019·Frontiers in Psychiatry·Meredith HalcombMelissa A Cyders
Nov 18, 2020·Biology of Sex Differences·Dany ArsenaultFrédéric Calon
May 13, 2021·Neuroscience and Biobehavioral Reviews·Nathan S PentkowskiBenjamin J Clark
Jul 13, 2021·Frontiers in Molecular Neuroscience·Xiaomin YinWei Qian
Aug 15, 2021·Ageing Research Reviews·Mohankumar AmirthalingamShinkichi Tawata
Apr 28, 2019·Neuroscience Letters·Nima N NaseriWenjie Luo

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Methods Mentioned

BETA
transgenic
ELISAs
ELISA
electrophoresis

Software Mentioned

Clampex
KODAK
Neurolucida
GraphPad
SAS
Clampfit
pClamp
Origin
OriginLab
prism

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