Cargando…

FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in a Mouse Model of Alzheimer’s Disease

The non-receptor focal adhesion kinase (FAK) is highly expressed in the central nervous system during development, where it regulates neurite outgrowth and axon guidance, but its role in the adult healthy and diseased brain, specifically in Alzheimer’s disease (AD), is largely unknown. Using the 3xT...

Descripción completa

Detalles Bibliográficos
Autores principales: Saleh, Bisan, Srikanth, Kolluru D., Sneh, Tal, Yue, Lambert, Pelech, Steven, Elliott, Evan, Gil-Henn, Hava
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9408823/
https://www.ncbi.nlm.nih.gov/pubmed/36012331
http://dx.doi.org/10.3390/ijms23169055
_version_ 1784774696357593088
author Saleh, Bisan
Srikanth, Kolluru D.
Sneh, Tal
Yue, Lambert
Pelech, Steven
Elliott, Evan
Gil-Henn, Hava
author_facet Saleh, Bisan
Srikanth, Kolluru D.
Sneh, Tal
Yue, Lambert
Pelech, Steven
Elliott, Evan
Gil-Henn, Hava
author_sort Saleh, Bisan
collection PubMed
description The non-receptor focal adhesion kinase (FAK) is highly expressed in the central nervous system during development, where it regulates neurite outgrowth and axon guidance, but its role in the adult healthy and diseased brain, specifically in Alzheimer’s disease (AD), is largely unknown. Using the 3xTg-AD mouse model, which carries three mutations associated with familial Alzheimer’s disease (APP KM670/671NL Swedish, PSEN1 M146V, MAPT P301L) and develops age-related progressive neuropathology including amyloid plaques and Tau tangles, we describe here, for the first time, the in vivo role of FAK in AD pathology. Our data demonstrate that while site-specific knockdown in the hippocampi of 3xTg-AD mice has no effect on learning and memory, hippocampal overexpression of the protein leads to a significant decrease in learning and memory capabilities, which is accompanied by a significant increase in amyloid β (Aβ) load. Furthermore, neuronal morphology is altered following hippocampal overexpression of FAK in these mice. High-throughput proteomics analysis of total and phosphorylated proteins in the hippocampi of FAK overexpressing mice indicates that FAK controls AD-like phenotypes by inhibiting cytoskeletal remodeling in neurons which results in morphological changes, by increasing Tau hyperphosphorylation, and by blocking astrocyte differentiation. FAK activates cell cycle re-entry and consequent cell death while downregulating insulin signaling, thereby increasing insulin resistance and leading to oxidative stress. Our data provide an overview of the signaling networks by which FAK regulates AD pathology and identify FAK as a novel therapeutic target for treating AD.
format Online
Article
Text
id pubmed-9408823
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-94088232022-08-26 FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in a Mouse Model of Alzheimer’s Disease Saleh, Bisan Srikanth, Kolluru D. Sneh, Tal Yue, Lambert Pelech, Steven Elliott, Evan Gil-Henn, Hava Int J Mol Sci Article The non-receptor focal adhesion kinase (FAK) is highly expressed in the central nervous system during development, where it regulates neurite outgrowth and axon guidance, but its role in the adult healthy and diseased brain, specifically in Alzheimer’s disease (AD), is largely unknown. Using the 3xTg-AD mouse model, which carries three mutations associated with familial Alzheimer’s disease (APP KM670/671NL Swedish, PSEN1 M146V, MAPT P301L) and develops age-related progressive neuropathology including amyloid plaques and Tau tangles, we describe here, for the first time, the in vivo role of FAK in AD pathology. Our data demonstrate that while site-specific knockdown in the hippocampi of 3xTg-AD mice has no effect on learning and memory, hippocampal overexpression of the protein leads to a significant decrease in learning and memory capabilities, which is accompanied by a significant increase in amyloid β (Aβ) load. Furthermore, neuronal morphology is altered following hippocampal overexpression of FAK in these mice. High-throughput proteomics analysis of total and phosphorylated proteins in the hippocampi of FAK overexpressing mice indicates that FAK controls AD-like phenotypes by inhibiting cytoskeletal remodeling in neurons which results in morphological changes, by increasing Tau hyperphosphorylation, and by blocking astrocyte differentiation. FAK activates cell cycle re-entry and consequent cell death while downregulating insulin signaling, thereby increasing insulin resistance and leading to oxidative stress. Our data provide an overview of the signaling networks by which FAK regulates AD pathology and identify FAK as a novel therapeutic target for treating AD. MDPI 2022-08-13 /pmc/articles/PMC9408823/ /pubmed/36012331 http://dx.doi.org/10.3390/ijms23169055 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Saleh, Bisan
Srikanth, Kolluru D.
Sneh, Tal
Yue, Lambert
Pelech, Steven
Elliott, Evan
Gil-Henn, Hava
FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in a Mouse Model of Alzheimer’s Disease
title FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in a Mouse Model of Alzheimer’s Disease
title_full FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in a Mouse Model of Alzheimer’s Disease
title_fullStr FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in a Mouse Model of Alzheimer’s Disease
title_full_unstemmed FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in a Mouse Model of Alzheimer’s Disease
title_short FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in a Mouse Model of Alzheimer’s Disease
title_sort fak-mediated signaling controls amyloid beta overload, learning and memory deficits in a mouse model of alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9408823/
https://www.ncbi.nlm.nih.gov/pubmed/36012331
http://dx.doi.org/10.3390/ijms23169055
work_keys_str_mv AT salehbisan fakmediatedsignalingcontrolsamyloidbetaoverloadlearningandmemorydeficitsinamousemodelofalzheimersdisease
AT srikanthkollurud fakmediatedsignalingcontrolsamyloidbetaoverloadlearningandmemorydeficitsinamousemodelofalzheimersdisease
AT snehtal fakmediatedsignalingcontrolsamyloidbetaoverloadlearningandmemorydeficitsinamousemodelofalzheimersdisease
AT yuelambert fakmediatedsignalingcontrolsamyloidbetaoverloadlearningandmemorydeficitsinamousemodelofalzheimersdisease
AT pelechsteven fakmediatedsignalingcontrolsamyloidbetaoverloadlearningandmemorydeficitsinamousemodelofalzheimersdisease
AT elliottevan fakmediatedsignalingcontrolsamyloidbetaoverloadlearningandmemorydeficitsinamousemodelofalzheimersdisease
AT gilhennhava fakmediatedsignalingcontrolsamyloidbetaoverloadlearningandmemorydeficitsinamousemodelofalzheimersdisease