Piezo1 Channels as Force Sensors in Mechanical Force-Related Chronic Inflammation

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Jan. 26, 2022

Mechanical damage is one of the predisposing factors inflammation, and it runs through entire inflammatory pathological process. Repeated or persistent damaging mechanical irritation leads to chronic diseases. The mechanism how forces induce inflammation not fully understood. Piezo1 a newly discovered mechanically sensitive ion channel. channel opens in response stimuli, transducing signals into an cascade cell leading tissue inflammation. A large amount evidence shows that plays vital role occurrence progression This mini-review briefly presents new responds different stresses trigger various tissues. discovery provides insights for treatment diseases related stress. Inhibiting transduction can inhibit improve outcome at early stage. pharmacology has shown bright prospects. development tissue-specific drugs clinical use may be target treating

Language: Английский

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The Potential Benefits of Quercetin for Brain Health: A Review of Anti-Inflammatory and Neuroprotective Mechanisms

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6328 - 6328

Published: March 28, 2023

Neuroinflammation is a critical factor in developing and progressing numerous brain diseases, including neurodegenerative diseases. Chronic or excessive neuroinflammation can lead to neurotoxicity, causing damage contributing the onset progression of various Therefore, understanding mechanisms strategies control them crucial for treating Studies have shown that plays vital role such as Alzheimer's (AD) Parkinson's (PD), stroke. Additionally, effects PM

Language: Английский

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Aducanumab—Hope or Disappointment for Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4367 - 4367

Published: Feb. 22, 2023

In June 2021, the world was informed about a new drug for Alzheimer’s disease approved by FDA. Aducanumab (BIIB037, ADU), being monoclonal antibody IgG1, is newest AD treatment. The activity of targeted towards amyloid β, which considered one main causes disease. Clinical trials have revealed time- and dose-dependent Aβ reduction, as well cognition improvement. Biogen, company responsible conducting research introducing to market, presents solution cognitive impairment, but its limitations, costs, side effects are controversial. framework paper focuses on mechanism aducanumab’s action along with positive negative sides therapy. review basis hypothesis that cornerstone therapy, latest information aducanumab, action, possibility use drug.

Language: Английский

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Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer’s disease

Cell Reports, Journal Year: 2025, Volume and Issue: unknown, P. 115109 - 115109

Published: Jan. 1, 2025

Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies infectious agents, with herpes simplex virus 1 (HSV-1) being leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression herpesvirus protein ICP27 increases severity strongly colocalizes p-tau but not Aβ. Modeling organoids shows that HSV-1 infection elevates phosphorylation. Notably, reduces expression markedly decreases post-infection neuronal death from 64% to 7%. This modeling prompts investigation into cGAS-STING-TBK1 pathway products, nuclear factor (NF)-κB IRF-3, which AD. Furthermore, experimental activation STING enhances phosphorylation, while TBK1 inhibition prevents it. Together, these findings suggest phosphorylation acts as an innate immune response AD, driven by cGAS-STING.

Language: Английский

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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, Journal Year: 2025, Volume and Issue: 14(2), P. 89 - 89

Published: Jan. 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

Language: Английский

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Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer’s disease, and late-onset Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: Jan. 18, 2025

Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar early-onset (EOAD) late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 4.07 (82.1 6.37 controls (66.4 13.04). identified differentially abundant proteins when comparing plaques neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in 132), 192), 128), 43 plaque-associated shared across all groups. Positive correlations were observed between (R2 .77), .73), .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p 1.29 × 10−5) for immune system regulation 4.33 lysosome organization 0.029) LOAD. Protein networks revealed a protein signature involving metabolism, response, functions. In vs. control tissue, we 263, 269, 301 proteins, 65 altered cohorts. Non-plaque showed modest .59) .33) compared correlation .79). GOBP term groups was chromatin remodeling 0.001), additional terms including extracellular matrix, protein–DNA complexes expression Our study reveals key functional characteristics amyloid LOAD, highlighting pathways endo/lysosomal functions responses. The distinct alterations ECM structure, underscoring unique differences subtypes. findings enhance our understanding pathogenesis identify potential biomarkers therapeutic targets.

Language: Английский

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Amyloid Cross-Seeding: Mechanism, Implication, and Inhibition

Molecules, Journal Year: 2022, Volume and Issue: 27(6), P. 1776 - 1776

Published: March 8, 2022

Most neurodegenerative diseases such as Alzheimer's disease, type 2 diabetes, Parkinson's etc. are caused by inclusions and plaques containing misfolded protein aggregates. These aggregates essentially formed the interactions of either same (homologous) or different (heterologous) sequences. Several experimental pieces evidence have revealed presence cross-seeding in amyloid proteins, which results a multicomponent assembly; however, molecular structural details remain less explored. Here, we discuss proteins phenomena detail. Data suggest that targeting common epitope interacting may be better therapeutic option than only one species. We also examine dual inhibitors target participating events. The future scopes major challenges understanding mechanism developing therapeutics considered. Detailed knowledge will stimulate further research practical aspects designing anti-amyloid therapeutics.

Language: Английский

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Cryo-EM structures of prion protein filaments from Gerstmann–Sträussler–Scheinker disease

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 144(3), P. 509 - 520

Published: July 12, 2022

Prion protein (PrP) aggregation and formation of PrP amyloid (APrP) are central events in the pathogenesis prion diseases. In dominantly inherited amyloidosis known as Gerstmann-Sträussler-Scheinker (GSS) disease, plaques made present throughout brain. The c.593t > c mutation gene (PRNP) results a phenylalanine to serine amino acid substitution at residue 198 (F198S) causes most severe among GSS variants. It has been shown that neurodegeneration this disease is associated with presence extracellular APrP neuronal intracytoplasmic Tau inclusions, have contain paired helical filaments identical those found Alzheimer disease. Using cryogenic electron microscopy (cryo-EM), we determined for first time structures human APrP, isolated post-mortem from brain two symptomatic PRNP F198S carriers. We report composed dimeric, trimeric tetrameric left-handed protofilaments their protomers sharing common fold. cross-β spines consist 62 acids span glycine 80 141, adopting previously unseen spiral fold thicker outer layer thinner inner layer. Each protomer comprises nine short β-strands, β1 β8 strands, well β4 β9 forming steric zipper. data obtained by cryo-EM provide insights into structural complexity filament amyloidosis. novel findings highlight urgency extending our knowledge filaments' may underlie distinct clinical pathologic phenotypes neurodegenerative

Language: Английский

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The link between metabolic syndrome and Alzheimer disease: A mutual relationship and long rigorous investigation

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 91, P. 102084 - 102084

Published: Oct. 5, 2023

Language: Английский

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Antibody-Mediated Clearance of Brain Amyloid-β: Mechanisms of Action, Effects of Natural and Monoclonal Anti-Aβ Antibodies, and Downstream Effects

Journal of Alzheimer s Disease Reports, Journal Year: 2023, Volume and Issue: 7(1), P. 873 - 899

Published: Aug. 7, 2023

Immunotherapeutic efforts to slow the clinical progression of Alzheimer’s disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither vaccination nor IVIG slowed progression. Despite conflicting phase III results, antibody Aducanumab received Food Drug Administration (FDA) approval for treatment AD in June 2021. The only treatments unequivocally demonstrated date are antibodies Lecanemab Donanemab. FDA January 2023 based on II results showing PET-detectable Aβ; released at that time indicated slowing Topline May Donanemab’s trial revealed primary secondary end points had been met. Antibody binding facilitates its clearance from via multiple mechanisms including promoting microglial phagocytosis, activating complement, dissolving fibrillar Aβ, antibody-Aβ complexes blood-brain barrier receptors. peripheral blood may also promote cerebral efflux a sink mechanism. According amyloid hypothesis, targeting progression, it must decrease downstream neuropathological processes tau aggregation phosphorylation (possibly) inflammation oxidative stress. This review discusses antibody-mediated clearance, findings trials involving IVIG, antibodies, effects reported those trials, approaches which might improve Aβ-clearing ability

Language: Английский

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