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RSS FeedsIJMS, Vol. 23, Pages 9055: FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in A Mouse Model of Alzheimer’s Disease (International Journal of Molecular Sciences)

 
 

13 august 2022 12:11:59

 
IJMS, Vol. 23, Pages 9055: FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in A Mouse Model of Alzheimer’s Disease (International Journal of Molecular Sciences)
 


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.


 
119 viewsCategory: Biochemistry, Biophysics, Molecular Biology
 
IJMS, Vol. 23, Pages 9067: Unique Features of the Tissue Structure in the Naked Mole Rat (Heterocephalus glaber): Hypertrophy of the Endoplasmic Reticulum and Spatial Mitochondrial Rearrangements in Hepatocytes (International Journal of Molecular Sciences)
IJMS, Vol. 23, Pages 9076: How to Use Respiratory Chain Inhibitors in Toxicology Studies—Whole-Cell Measurements (International Journal of Molecular Sciences)
 
 
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