Combined Inhibition of Fyn and c-Src Protects Hippocampal Neurons and Improves Spatial Memory via ROCK after Traumatic Brain Injury

Ye, Zhouheng; Izadi, Ali; Gurkoff, Gene G.; Rickerl, Kaitlin; Sharp, Frank R.; Ander, Bradley P.; Bauer, Sawyer Z.; Lui, Austin; Lyeth, Bruce G.; Liu, Dazhi

doi:10.1089/neu.2021.0311

Cited by 7 publications

(3 citation statements)

References 36 publications

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“…ROS-responsive ASK1 phosphorylates JIP-3 to enhance scaffolding interactions with SEK1/MKK4, MKK7, and downstream JNK3, promoting neurodegenerative JNK3 activation [64]. Consistent with a role in our model, TBI induces Rock1-dependent neurodegeneration [65] and phosphorylation at three sites in JIP-3:Ser 318 , Ser 368 , and Ser 369 [66], resulting in JNK activation. Gap43 is well known as a primary JNK-targeted axonal phospho-protein [67] with elevations in AD CSF associated with tauopathy that predict progression [68].…”

Section: Turquoise Modulesupporting

confidence: 84%

The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression

Jackson,

Chen,

Nguyen

et al. 2024

IJMS

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Blast-induced neurotrauma (BINT) is a pressing concern for veterans and civilians exposed to explosive devices. Affected personnel may have increased risk for long-term cognitive decline and developing tauopathies including Alzheimer’s disease-related disorders (ADRD) or frontal-temporal dementia (FTD). The goal of this study was to identify the effect of BINT on molecular networks and their modulation by mutant tau in transgenic (Tg) mice overexpressing the human tau P301L mutation (rTg4510) linked to FTD or non-carriers. The primary focus was on the phosphoproteome because of the prominent role of hyperphosphorylation in neurological disorders. Discrimination learning was assessed following injury in the subsequent 6 weeks, using the automated home-cage monitoring CognitionWall platform. At 40 days post injury, label-free phosphoproteomics was used to evaluate molecular networks in the frontal cortex of mice. Utilizing a weighted peptide co-expression network analysis (WpCNA) approach, we identified phosphopeptide networks tied to associative learning and mossy-fiber pathways and those which predicted learning outcomes. Phosphorylation levels in these networks were inversely related to learning and linked to synaptic dysfunction, cognitive decline, and dementia including Atp6v1a and Itsn1. Low-intensity blast (LIB) selectively increased pSer262tau in rTg4510, a site implicated in initiating tauopathy. Additionally, individual and group level analyses identified the Arhgap33 phosphopeptide as an indicator of BINT-induced cognitive impairment predominantly in rTg4510 mice. This study unveils novel interactions between ADRD genetic susceptibility, BINT, and cognitive decline, thus identifying dysregulated pathways as targets in potential precision-medicine focused therapeutics to alleviate the disease burden among those affected by BINT.

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Section: Turquoise Modulesupporting

confidence: 84%

The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression

Jackson,

Chen,

Nguyen

et al. 2024

IJMS

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“…In vertebrates, the Src kinase family is composed of nine members: SRC, LCK, LYN, BLK, HCK, FYN, FGR, YES, and YRK. Among them, FYN, SRC, and LYN are distributed throughout the brain ( 30 , 31 ). To further the kinase(s) involved in this process, we transfected siRNA for each kinase into neurons for 48 h to interfere with their expression.…”

Section: Resultsmentioning

confidence: 99%

Brain-derived neurotrophic factor regulates LYN kinase–mediated myosin light chain kinase activation to modulate nonmuscle myosin II activity in hippocampal neurons

Yuan

Wang

et al. 2022

Journal of Biological Chemistry

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“…Using the Rho cascade as an example, previous studies have shown that the Rho GTPase signaling pathway is associated with many neuronal functions, such as dendrite development, migration, and axonal extension. 65 In addition, Ye et al reported that Rho-associated protein kinase could contribute to cell death and cognitive dysfunction after TBI. 66 Therefore, the inhibition of Rho signaling pathway mediated by miRNA, as discovered in this study, is likely to be the key node for the reduction of pathological damage and improvement of functional outcome after TBI treatment using Duo-Exo@NF.…”

Section: Histopathological Evaluation In Tbi Micementioning

confidence: 99%

Local Delivery of Dual Stem Cell-Derived Exosomes Using an Electrospun Nanofibrous Platform for the Treatment of Traumatic Brain Injury

Li,

et al. 2024

ACS Appl. Mater. Interfaces

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Traumatic brain injury poses serious physical, psychosocial, and economic threats. Although systemic administration of stem cell-derived exosomes has recently been proven to be a promising modality for traumatic brain injury treatment, they come with distinct drawbacks. Luckily, various biomaterials have been developed to assist local delivery of exosomes to improve the targeting of organs, minimize nonspecific accumulation in vital organs, and ensure the protection and release of exosomes. In this study, we developed an electrospun nanofibrous scaffold to provide sustained delivery of dual exosomes derived from mesenchymal stem cells and neural stem cells for traumatic brain injury treatment. The electrospun nanofibrous scaffold employed a functionalized layer of polydopamine on electrospun poly(εcaprolactone) nanofibers, thereby enhancing the efficient incorporation of exosomes through a synergistic interplay of adhesive forces, hydrogen bonding, and electrostatic interactions. First, the mesenchymal stem cell-derived exosomes and the neural stem cellderived exosomes were found to modulate microglial polarization toward M2 phenotype, play an important role in the modulation of inflammatory responses, and augment axonal outgrowth and neural repair in PC12 cells. Second, the nanofibrous scaffold loaded with dual stem cell-derived exosomes (Duo-Exo@NF) accelerated functional recovery in a murine traumatic brain injury model, as it mitigated the presence of reactive astrocytes and microglia while elevating the levels of growth associated protein-43 and doublecortin. Additionally, multiomics analysis provided mechanistic insights into how dual stem cell-derived exosomes exerted its therapeutic effects. These findings collectively suggest that our novel Duo-Exo@NF system could function as an effective treatment modality for traumatic brain injury using sustained local delivery of dual exosomes from stem cells.

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Combined Inhibition of Fyn and c-Src Protects Hippocampal Neurons and Improves Spatial Memory via ROCK after Traumatic Brain Injury

Cited by 7 publications

References 36 publications

The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression

The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression

Brain-derived neurotrophic factor regulates LYN kinase–mediated myosin light chain kinase activation to modulate nonmuscle myosin II activity in hippocampal neurons

Local Delivery of Dual Stem Cell-Derived Exosomes Using an Electrospun Nanofibrous Platform for the Treatment of Traumatic Brain Injury

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