PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβ
Defects in p21-activated kinase (PAK) are suspected to play a role in cognitive symptoms of Alzheimer's disease (AD). Dysfunction in PAK leads to cofilin activation, drebrin displacement from its actin-binding site, actin depolymerization/severing, and, ultimately, defects in spine dynamics and...
| Main Authors: | , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Society for Neuroscience
2014
|
| Online Access: | http://hdl.handle.net/1721.1/85179 https://orcid.org/0000-0003-2839-8228 |
| _version_ | 1811088799781879808 |
|---|---|
| author | Tonegawa, Susumu Arsenault, Dany Dal-Pan, Alexandre Tremblay, Cyntia Bennett, David A. Guitton, Matthieu J. De Koninck, Yves Calon, Frederic |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Tonegawa, Susumu Arsenault, Dany Dal-Pan, Alexandre Tremblay, Cyntia Bennett, David A. Guitton, Matthieu J. De Koninck, Yves Calon, Frederic |
| author_sort | Tonegawa, Susumu |
| collection | MIT |
| description | Defects in p21-activated kinase (PAK) are suspected to play a role in cognitive symptoms of Alzheimer's disease (AD). Dysfunction in PAK leads to cofilin activation, drebrin displacement from its actin-binding site, actin depolymerization/severing, and, ultimately, defects in spine dynamics and cognitive impairment in mice. To determine the role of PAK in AD, we first quantified PAK by immunoblotting in homogenates from the parietal neocortex of subjects with a clinical diagnosis of no cognitive impairment (n = 12), mild cognitive impairment (n = 12), or AD (n = 12). A loss of total PAK, detected in the cortex of AD patients (−39% versus controls), was correlated with cognitive impairment (r[superscript 2] = 0.148, p = 0.027) and deposition of total and phosphorylated tau (r[superscript 2] = 0.235 and r[superscript 2] = 0.206, respectively), but not with Aβ42 (r[superscript 2] = 0.056). Accordingly, we found a decrease of total PAK in the cortex of 12- and 20-month-old 3xTg-AD mice, an animal model of AD-like Aβ and tau neuropathologies. To determine whether PAK dysfunction aggravates AD phenotype, 3xTg-AD mice were crossed with dominant-negative PAK mice. PAK inactivation led to obliteration of social recognition in old 3xTg-AD mice, which was associated with a decrease in cortical drebrin (−25%), but without enhancement of Aβ/tau pathology or any clear electrophysiological signature. Overall, our data suggest that PAK decrease is a consequence of AD neuropathology and that therapeutic activation of PAK may exert symptomatic benefits on high brain function. |
| first_indexed | 2024-09-23T14:07:44Z |
| format | Article |
| id | mit-1721.1/85179 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:07:44Z |
| publishDate | 2014 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/851792022-09-28T18:40:34Z PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβ Tonegawa, Susumu Arsenault, Dany Dal-Pan, Alexandre Tremblay, Cyntia Bennett, David A. Guitton, Matthieu J. De Koninck, Yves Calon, Frederic Massachusetts Institute of Technology. Department of Biology Tonegawa, Susumu Defects in p21-activated kinase (PAK) are suspected to play a role in cognitive symptoms of Alzheimer's disease (AD). Dysfunction in PAK leads to cofilin activation, drebrin displacement from its actin-binding site, actin depolymerization/severing, and, ultimately, defects in spine dynamics and cognitive impairment in mice. To determine the role of PAK in AD, we first quantified PAK by immunoblotting in homogenates from the parietal neocortex of subjects with a clinical diagnosis of no cognitive impairment (n = 12), mild cognitive impairment (n = 12), or AD (n = 12). A loss of total PAK, detected in the cortex of AD patients (−39% versus controls), was correlated with cognitive impairment (r[superscript 2] = 0.148, p = 0.027) and deposition of total and phosphorylated tau (r[superscript 2] = 0.235 and r[superscript 2] = 0.206, respectively), but not with Aβ42 (r[superscript 2] = 0.056). Accordingly, we found a decrease of total PAK in the cortex of 12- and 20-month-old 3xTg-AD mice, an animal model of AD-like Aβ and tau neuropathologies. To determine whether PAK dysfunction aggravates AD phenotype, 3xTg-AD mice were crossed with dominant-negative PAK mice. PAK inactivation led to obliteration of social recognition in old 3xTg-AD mice, which was associated with a decrease in cortical drebrin (−25%), but without enhancement of Aβ/tau pathology or any clear electrophysiological signature. Overall, our data suggest that PAK decrease is a consequence of AD neuropathology and that therapeutic activation of PAK may exert symptomatic benefits on high brain function. 2014-02-28T14:11:40Z 2014-02-28T14:11:40Z 2013-06 2013-05 Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/85179 Arsenault, D. et al. “PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and A.” Journal of Neuroscience 33.26 (2013): 10729–10740. https://orcid.org/0000-0003-2839-8228 en_US http://dx.doi.org/10.1523/JNEUROSCI.1501-13.2013 Journal of Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Society for Neuroscience Society for Neuroscience |
| spellingShingle | Tonegawa, Susumu Arsenault, Dany Dal-Pan, Alexandre Tremblay, Cyntia Bennett, David A. Guitton, Matthieu J. De Koninck, Yves Calon, Frederic PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβ |
| title | PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβ |
| title_full | PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβ |
| title_fullStr | PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβ |
| title_full_unstemmed | PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβ |
| title_short | PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβ |
| title_sort | pak inactivation impairs social recognition in 3xtg ad mice without increasing brain deposition of tau and aβ |
| url | http://hdl.handle.net/1721.1/85179 https://orcid.org/0000-0003-2839-8228 |
| work_keys_str_mv | AT tonegawasusumu pakinactivationimpairssocialrecognitionin3xtgadmicewithoutincreasingbraindepositionoftauandab AT arsenaultdany pakinactivationimpairssocialrecognitionin3xtgadmicewithoutincreasingbraindepositionoftauandab AT dalpanalexandre pakinactivationimpairssocialrecognitionin3xtgadmicewithoutincreasingbraindepositionoftauandab AT tremblaycyntia pakinactivationimpairssocialrecognitionin3xtgadmicewithoutincreasingbraindepositionoftauandab AT bennettdavida pakinactivationimpairssocialrecognitionin3xtgadmicewithoutincreasingbraindepositionoftauandab AT guittonmatthieuj pakinactivationimpairssocialrecognitionin3xtgadmicewithoutincreasingbraindepositionoftauandab AT dekoninckyves pakinactivationimpairssocialrecognitionin3xtgadmicewithoutincreasingbraindepositionoftauandab AT calonfrederic pakinactivationimpairssocialrecognitionin3xtgadmicewithoutincreasingbraindepositionoftauandab |