Biphasic modulation of tau liquid–liquid phase separation by polyphenols

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(32), P. 4334 - 4337

Published: Jan. 1, 2024

Polyphenols, notably gallic acid (GA), act as a biphasic modulator of tau liquid–liquid phase separation in concentration-dependent manner. GA accelerates the sol-to-gel transition and inhibits aggregate-associated toxicity.

Language: Английский

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Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients

Theranostics, Journal Year: 2023, Volume and Issue: 13(12), P. 4102 - 4120

Published: Jan. 1, 2023

Rationale: Bilateral sonication with focused ultrasound (FUS) in conjunction microbubbles has been shown to separately reduce amyloid plaques and hyperphosphorylated tau protein the hippocampal formation entorhinal cortex different mouse models of Alzheimer's disease (AD) without any therapeutic agents.However, two pathologies are expressed concurrently human disease.Therefore, objective this study is investigate effects repeated bilateral sonications presence both pathologies.Methods: Herein, we its functional morphological outcomes on brains bearing simultaneously.Eleven transgenic mice 3xTg-AD line (14 months old) expressing beta eleven age-matched wild-type littermates received four weekly covering hippocampus followed by working memory testing.Afterwards, immunohistochemistry immunoassays (western blot ELISA) were employed assess changes tau.Furthermore, present preliminary data from our clinical trial using a neuronavigation-guided FUS system for AD patients (NCT04118764).Results: Interestingly, animals that experienced improved spent significantly more time escape platform-quadrant, spending 43.2% (sham: 37.7%) 35.3%(sham: 31.0%) target quadrant.Furthermore, behavioral amelioration correlated 58.3% decrease neuronal length affected 27.2% reduction total levels.Amyloid plaque population, volume overall load also reduced overall.Consistently, involving showed 1.8% PET signal 3-weeks after treatment treated hemisphere compared baseline.Conclusion: For first time, it FUS-induced BBB opening simultaneously ameliorates coexistent pathologies, which translated improvements spatial complex AD, mimicking phenotype.The level cognitive improvement was opening.Non-transgenic exhibit similar indicating results into benefits function regardless existence pathology.A potential mechanism action investigated cholesterol metabolism, specifically LRP1b receptor, exhibited increased expression levels following opening.Initial evidence supported rodents could be translatable humans significant hemisphere.

Language: Английский

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In Vivo Near-Infrared Fluorescence Imaging Selective for Soluble Amyloid β Aggregates Using y-Shaped BODIPY Derivative

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(20), P. 14029 - 14046

Published: Oct. 12, 2023

Soluble amyloid β (Aβ) aggregates, suggested to be the most toxic forms of Aβ, draw attention as therapeutic targets and biomarkers Alzheimer's disease (AD). As soluble Aβ aggregates are transient diverse, imaging their diverse in vivo is expected have a marked impact on research diagnosis AD. Herein, we report near-infrared fluorescent (NIRF) probe, BAOP-16, targeting aggregates. whose molecular shape resembles "y", showed selective increase fluorescence intensity upon binding region high affinity for them. Additionally, BAOP-16 could detect oligomers brains Aβ-inoculated model mice. In an study AD mice displayed significantly higher signals than those wild-type These results indicate that useful NIRF

Language: Английский

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Combined strategies for optimizing BODIPY-based near-infrared fluorescent probe targeting Aβ oligomers

Sensors and Actuators B Chemical, Journal Year: 2024, Volume and Issue: 417, P. 136132 - 136132

Published: June 11, 2024

Language: Английский

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Application of biomarker-derived fluorescent probes for the detection of Alzheimer's disease

TrAC Trends in Analytical Chemistry, Journal Year: 2023, Volume and Issue: 169, P. 117369 - 117369

Published: Oct. 12, 2023

Language: Английский

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The potential anti-Alzheimer's activity of Oxalis corniculata Linn. Methanolic extract in experimental rats: Role of APOE4/LRP1, TLR4/NF-κβ/NLRP3, Wnt 3/β-catenin/GSK-3β, autophagy and apoptotic cues

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 324, P. 117731 - 117731

Published: Jan. 11, 2024

Oxalis corniculata (O. corniculata) is a member of Oxalidaceae family, widely distributed in Asia, Europe, America, and Africa, used extensively as food its traditional folkloric uses include management epilepsy, gastric disorders, neurodegenerative diseases, together with use enhancing health. Numerous pharmacological benefits O. are linked to anti-inflammatory antioxidant abilities. One the most prevalent disorders Alzheimer's disease (AD) which neuroinflammation oxidative stress main pathogenic processes. Our research aimed study neuroprotective effect methanolic extract Linn. ME), compared selenium (Se) against AlCl3-induced AD. Forty male albino rats were allocated into four groups (Gps). Gp I control group, rest animals received AlCl3 (Gp II-Gp IV). Rats III IV treated Se ME, respectively. The chemical profile ME was studied using ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry, allowing tentative identification sixty-six compounds, including organic acids, phenolics others, cinnamic acid derivatives, fatty flavonoids. showed deterioration short-term memory brain histological pictures. findings that helped combat produced by accumulation prophylaxis Thus, Selenium restored defense, via Nrf2/HO-1 hub, hampered neuroinflammation, TLR4/NF-κβ/NLRP3, along dampening apoptosis, Aβ generation, tau hyperphosphorylation, BACE1, ApoE4 LRP1 levels. Treatments also promoted autophagy modulated Wnt 3/β-catenin/GSK3β cue. It noted notable ameliorative on Nrf2/HO-1, APOE4/LRP1, 3/β-catenin/GSK-3β PERK axes.

Language: Английский

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A facile two-photon red-emission fluorescent marker with a large Stokes shift for in vivo brain imaging of amyloid-beta aggregates

Cell Reports Physical Science, Journal Year: 2024, Volume and Issue: 5(2), P. 101810 - 101810

Published: Feb. 1, 2024

Efficient fluorescent probes for brain imaging of the progressive changes amyloid-beta (Aβ) aggregates in Alzheimer's disease (AD) are highly desired to track occurrence and development AD. Herein, a donor-acceptor-donor-type probe (BTD-Aβ) is prepared using benzothiadiazole (BTD) scaffold as acceptor, together with p-dimethylaminobenzene p-hydroxybenzene donors. The an electrically neutral molecule low molecular weight 348.1 Da, large two-photon absorption cross-section 240 Goeppert-Mayer, red emission centered at 630 nm, Stokes shift 200 nm. In addition, displays improved sensing capabilities Aβ including faster response (within 12 min), higher binding affinity (Kd = 374 nM), selectivity, good blood-brain barrier penetration (16.0%). successfully used situ observation Aβ42 aggregating brain-derived endothelial cells vivo AD mice.

Language: Английский

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Dietary supplementation and the role of phytochemicals against the Alzheimer's disease: Focus on polyphenolic compounds

The Journal of Prevention of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: 12(1), P. 100004 - 100004

Published: Jan. 1, 2025

Alzheimer's disease is a complicated, multifaceted, neurodegenerative illness that places an increasing strain on healthcare systems. Due to malfunction and death of nerve cells, the person suffering from (AD) slowly steadily loses their memories, cognitive functions even personality. Although medications may temporarily enhance memory, there are currently no permanent therapies can halt or cure this irreversible process. Nonetheless, fast progress in comprehending cellular molecular abnormalities responsible for neuronal degeneration has increased confidence development viable prevention treatments. All FDA-approved anti-AD have merely symptomatic effects cannot illness. This necessitates pursuit alternate Accumulating data shows systemic neuroinflammation, oxidative stress associated mitochondrial dysfunction play crucial roles etiology AD precede its clinical presentation. Therefore, innovative therapeutic approaches targeting these pathophysiological components being explored aggressively present scenario. Phytochemicals such as resveratrol, curcumin, quercetin, genistein catechins prospective owing capacity alter key pathogenetic pathways, stress, dysfunction. The use new phytochemical delivery strategies would certainly provide possibility solve several issues with standard medicines. In review, phytophenolic compound-based treatment discussed.

Language: Английский

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Strategic Mutations in Designer Native Peptides Combat NLRP3 Inflammasome Activation in Neurodegenerative Disorders

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin (PYD)-containing protein 3 (NLRP3) form an inflammasome by assembling with apoptosis-associated speck-like containing a CARD (ASC) procaspase-1 that plays pivotal role in various neurodegenerative diseases such as Alzheimer's Parkinson diseases. We designed native peptides derived from the PYDs of NLRP3 ASC based on their interfacial interaction to inhibit formation. Screening revealed NP3, NLRP3, inhibits activation. Furthermore, strategic mutation (F → L) peptide NP3 results MNP2 selectively binds PYD nanomolar affinity, inhibiting formation, interleukin-1β (IL-1β) release, caspase-1 maturation. also reduced potassium (K) chloride (Cl) ion efflux, key signals activation, prevented mitochondrial damage reactive oxygen species (ROS) production. significantly formation conditions triggered amyloid-β (Aβ), Tau, α-Synuclein (α-Syn), suggesting promising therapeutic strategy for NLRP3-related inflammatory diseases, including disorders.

Language: Английский

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Zn(ii)-driven impact of monomeric transthyretin on amyloid-β amyloidogenesis

Chemical Science, Journal Year: 2025, Volume and Issue: 16(10), P. 4366 - 4373

Published: Jan. 1, 2025

Zn( ii ) coordination to monomeric transthyretin (M-TTR) forms a ternary complex with amyloid-β (Aβ) peptides and promotes their hydrolysis, which directs M-TTR's anti-amyloidogenic activity through inhibiting primary nucleation.

Language: Английский

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