Molecular Mechanisms of Alzheimer’s Disease Induced by Amyloid-β and Tau Phosphorylation Along with RhoA Activity: Perspective of RhoA/Rho-Associated Protein Kinase Inhibitors for Neuronal Therapy

Cells, Год журнала: 2025, Номер 14(2), С. 89 - 89

Опубликована: Янв. 10, 2025

Amyloid-β peptide (Aβ) is a critical cause of Alzheimer's disease (AD). It generated from amyloid precursor protein (APP) through cleavages by β-secretase and γ-secretase. γ-Secretase, which includes presenilin, regulated several stimuli. Tau has also been identified as significant factor in AD. In particular, phosphorylation crucial for neuronal impairment, phosphorylated detaches microtubules, leading to the formation neurofibrillary tangles destabilization microtubule structure. This instability microtubules damages axons dendrites, resulting impairment. Notably, Aβ linked phosphorylation. Another AD neuroinflammation, primarily occurring microglia. Microglia possess receptors that bind with Aβ, triggering expression release an inflammatory factor, although their main physiological function phagocytose debris pathogens brain. NF-κB activation plays major role neuroinflammation. Additionally, production reactive oxygen species (ROS) microglia contributes this microglia, superoxide produced NADPH oxidase, specifically NOX2. Rho GTPases play essential regulating various cellular processes, including cytoskeletal rearrangement, morphology changes, migration, transcription. The typical involves actin filament formation. Neurons, complex processes synapse connections, rely on dynamics structural support. Other brain cells, such astrocytes, oligodendrocytes, depend specific structures maintain unique architectures. Thus, aberrant regulation activity can disrupt filaments, altered cell morphology, changes synapses, potentially contributing diseases

Язык: Английский

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Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK

Biophysical Reviews, Год журнала: 2023, Номер 15(2), С. 163 - 181

Опубликована: Апрель 1, 2023

Neurodevelopmental disorders (NDDs) and cancer share proteins, pathways, mutations. Their clinical symptoms are different. However, individuals with NDDs have higher probabilities of eventually developing cancer. Here, we review the literature ask how shared features can lead to different medical conditions why having an NDD first increase chances malignancy. To explore these vital questions, focus on dysregulated PI3K/mTOR, a major brain cell growth pathway in differentiation, MAPK, critical proliferation, hallmark Differentiation is governed by chromatin organization, making aberrant remodelers highly likely agents NDDs. Dysregulated organization accessibility influence lineage specific types at embryonic development stages. PAK1, pivotal roles cancer, also regulates MAPK. We review, clarify, connect pathways proliferation differentiation highlight PAK1 role MAPK regulation. Exactly activation controls development, remodeler components, e.g., BAF170 encoded

Язык: Английский

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Breaking barriers: exploring mechanisms behind opening the blood–brain barrier

Fluids and Barriers of the CNS, Год журнала: 2023, Номер 20(1)

Опубликована: Ноя. 28, 2023

The blood-brain barrier (BBB) is a selectively permeable membrane that separates the bloodstream from brain. While useful for protecting neural tissue harmful substances, brain-related diseases are difficult to treat due this barrier, as it also limits efficacy of drug delivery. To address this, promising new approaches enhancing delivery based on disrupting BBB using physical means, including optical/photothermal therapy, electrical stimulation, and acoustic/mechanical stimulation. These mechanisms can temporarily locally open BBB, allowing drugs other substances enter. Focused ultrasound particularly promising, with ability focus energies targeted, deep-brain regions. In review, we examine recent advances in temporary disruption, describing their underlying well evaluating utility these regard potential risks limitations. methods have demonstrated safety, comparative efficacy, practicality clinical use remain an ongoing topic research.

Язык: Английский

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The Molecular Pathway of p75 Neurotrophin Receptor (p75NTR) in Parkinson’s Disease: The Way of New Inroads

Molecular Neurobiology, Год журнала: 2023, Номер 61(5), С. 2469 - 2480

Опубликована: Окт. 28, 2023

Язык: Английский

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A current overview of RhoA, RhoB, and RhoC functions in vascular biology and pathology

Biochemical Pharmacology, Год журнала: 2022, Номер 206, С. 115321 - 115321

Опубликована: Окт. 26, 2022

Язык: Английский

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ICAM-1 Deletion Using CRISPR/Cas9 Protects the Brain from Traumatic Brain Injury-Induced Inflammatory Leukocyte Adhesion and Transmigration Cascades by Attenuating the Paxillin/FAK-Dependent Rho GTPase Pathway

Journal of Neuroscience, Год журнала: 2024, Номер 44(11), С. e1742232024 - e1742232024

Опубликована: Фев. 7, 2024

Intercellular adhesion molecule-1 (ICAM-1) is identified as an initiator of neuroinflammatory responses that lead to neurodegeneration and cognitive sensory–motor deficits in several pathophysiological conditions including traumatic brain injury (TBI). However, the underlying mechanisms ICAM-1–mediated leukocyte transmigration its link with neuroinflammation functional following TBI remain elusive. Here, we hypothesize blocking ICAM-1 attenuates leukocytes promotes recovery after TBI. The experimental was induced vivo by fluid percussion (25 psi) male female wild-type −/− mice vitro stretch (3 human microvascular endothelial cells (hBMVECs). We treated hBMVECs animals CRISPR/Cas9 conducted biochemical analyses demonstrated CRISPR/Cas9-mediated deletion mitigates blood–brain barrier (BBB) damage attenuating paxillin/focal kinase (FAK)-dependent Rho GTPase pathway. For analyzing outcomes, used a cohort behavioral tests included sensorimotor functions, psychological stress analyses, spatial memory learning In conclusion, this study could establish significance or transforming into novel preventive approach against pathophysiology

Язык: Английский

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Oligomeric Tau-induced oxidative damage and functional alterations in cerebral endothelial cells: Role of RhoA/ROCK signaling pathway

Free Radical Biology and Medicine, Год журнала: 2024, Номер 221, С. 261 - 272

Опубликована: Май 28, 2024

Despite of yet unknown mechanism, microvascular deposition oligomeric Tau (oTau) has been implicated in alteration the Blood-Brain Barrier (BBB) function Alzheimer's disease (AD) brains. In this study, we employed an vitro BBB model using primary mouse cerebral endothelial cells (CECs) to investigate mechanism underlying effects oTau on function. We found that exposing CECs induced oxidative stress through NADPH oxidase, increased damage proteins, decreased proteasome activity, and expressions tight junction (TJ) proteins including occludin, zonula occludens-1 (ZO-1) claudin-5. These were suppressed by pretreatment with Fasudil, a RhoA/ROCK signaling inhibitor. Consistent biochemical alterations, basolateral side disrupted integrity BBB, as indicated increase FITC-dextran transport across model, decrease trans electrical resistance (TEER). also transmigration peripheral blood mononuclear (PBMCs) model. functional alterations Fasudil. Taken together, our findings suggest targeting pathway can be potential therapeutic strategy maintain AD.

Язык: Английский

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Human Breast Milk microRNAs, Potential Players in the Regulation of Nervous System

Nutrients, Год журнала: 2023, Номер 15(14), С. 3284 - 3284

Опубликована: Июль 24, 2023

Human milk is the biological fluid with highest exosome amount and rich in microRNAs (miRNAs). These are key regulators of gene expression networks both normal physiologic disease contexts, miRNAs can influence many processes have also shown promise as biomarkers for disease. One aspects regeneration nervous system that there practically no molecules be used potential drugs. In first weeks lactation, we know human breast must contain mechanisms to transmit molecular information brain development. For this reason, our objective identify new modulators investigate neurodevelopmental functions based on miRNAs. To do this, collected samples according time delivery states: mature colostrum at term; moderate very preterm colostrum; late milk. We extracted exosomes realized miRNA functional assays target prediction. Our results demonstrate abundant likely play significant roles neurodevelopment function. found 132 different were identified across all samples. Sixty-nine had differential after paired group comparison. implicated regulation dopaminergic/glutamatergic synapses neurotransmitter secretion related process regulates neuron projection morphogenesis synaptic vesicle transport. observed differences less clarity type. data

Язык: Английский

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Role of Rho-Associated Kinase in the Pathophysiology of Cerebral Cavernous Malformations

Neurology Genetics, Год журнала: 2024, Номер 10(1)

Опубликована: Янв. 3, 2024

Cerebral cavernous malformations (CCMs) are vascular lesions characterized by a porous endothelium. The lack of sufficient endothelial barrier can result in microbleeds and frank intracerebral hemorrhage. A primary mechanism for lesion development is sequence variant at least 1 the 3 CCM genes (

Язык: Английский

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Allosteric Activation of RhoA Complexed with p115-RhoGEF Deciphered by Conformational Dynamics

Journal of Chemical Information and Modeling, Год журнала: 2024, Номер 64(3), С. 862 - 873

Опубликована: Янв. 12, 2024

The Ras homologue family member A (RhoA) is a of the Rho family, subgroup superfamily. RhoA interacts with 115 kDa guanine nucleotide exchange factor (p115-RhoGEF), which assists in activation and binding downstream effectors. Here, we use molecular dynamics (MD) simulations essential analysis inactive RhoA–GDP active RhoA–GTP, when bound to p115-RhoGEF decipher mechanism at structural level. We observe that maintains its position near catalytic site on Dbl homology (DH) domain through interaction Switch I region DH domain. further show RhoA–GTP engaged more interactions membrane-bound Pleckstrin (PH) as compared RhoA–GDP. hypothesize role between PH help release it from upon activation. Our results support this premise, our uncover beginning process provide details. They also point allosteric communication pathways take part promote strengthen Allosteric regulation occurs among other members Collectively, suggest process, after activation, making available

Язык: Английский

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