Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(3), P. 952 - 952

Published: Jan. 31, 2020

Worldwide, Alzheimer’s disease (AD) is the most common age-related neurodegenerative and characterized by unique pathological hallmarks in brain, including plaques composed of amyloid β-protein (Aβ) neurofibrillary tangles tau protein. Genetic studies, biochemical data, animal models have suggested that Aβ responsible for pathogenesis AD (i.e., hypothesis). Indeed, molecules tend to aggregate, forming oligomers, protofibrils, mature fibrils. However, while these species form type implicated neurodegeneration, recent clinical trials designed reduce production and/or plaque burden not demonstrated efficacy. In addition, studies using synthetic peptides, cell culture models, Arctic transgenic mice, human samples brain tissues pre-fibrillar forms Aβ, particularly may be critical species, compared with extracellular fibrillar forms. We recently reported protofibrils Aβ1-42 disturbed membrane integrity inducing reactive oxygen generation lipid peroxidation, resulting decreased fluidity, intracellular calcium dysregulation, depolarization, synaptic toxicity. Therefore, therapeutic reduction prevent progression ameliorating neuronal damage cognitive dysfunction through multiple mechanisms.

Language: Английский

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Myricetin prevents high molecular weight Aβ1-42 oligomer-induced neurotoxicity through antioxidant effects in cell membranes and mitochondria

Free Radical Biology and Medicine, Journal Year: 2021, Volume and Issue: 171, P. 232 - 244

Published: May 17, 2021

Language: Английский

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Amyloid β interaction with model cell membranes – What are the toxicity-defining properties of amyloid β?

International Journal of Biological Macromolecules, Journal Year: 2022, Volume and Issue: 200, P. 520 - 531

Published: Jan. 21, 2022

Disruption of the neuronal membrane by toxic amyloid β oligomers is hypothesized to be major event associated with Alzheimer's disease's neurotoxicity. Misfolding followed aggregation via different pathways in which structurally can formed. The respective actions these diverse vary significantly. Linking a particular action unique kind and resolving their toxicity-determining feature remains challenging because transient stability heterogeneity. Moreover, lipids that make up affect oligomers' behavior, thus adding problem's complexity. present review compares analyzes latest results improve understanding interaction lipid bilayers.

Language: Английский

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Constituent isoflavones of Puerariae radix as a potential neuroprotector in cognitive impairment: Evidence from preclinical studies

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 90, P. 102040 - 102040

Published: Aug. 23, 2023

Language: Английский

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Rational Design of Dual-Functionalized Gd@C₈₂ Nanoparticles to Relieve Neuronal Cytotoxicity in Alzheimer’s Disease via Inhibition of Aβ Aggregation

ACS Nano, Journal Year: 2024, Volume and Issue: 18(24), P. 15416 - 15431

Published: June 5, 2024

The accumulation of amyloid-β (Aβ) peptides is a major hallmark Alzheimer's disease (AD) and plays crucial role in its pathogenesis. Particularly, the structured oligomeric species rich β-sheet formations were implicated neuronal organelle damage. Addressing this formidable challenge requires identifying candidates capable inhibiting peptide aggregation or disaggregating preformed oligomers for effective antiaggregation-based AD therapy. Here, we present dual-functional nanoinhibitor meticulously designed to target driving force amyloid fibril spatial structure. Leveraging exceptional structural stability facile tailoring capability endohedral metallofullerene Gd@C82, introduce desired hydrogen-binding sites charged groups, which are abundant on surface specific designs. Impressively, these designs endow resultant functionalized-Gd@C82 nanoparticles (f-Gd@C82 NPs) with high redirecting self-assembly toward disordered, off-pathway species, obstructing early growth protofibrils, well-ordered protofibrils even mature Aβ fibrils. This results considerable alleviation peptide-induced cytotoxicity, rescuing death synaptic loss primary neuron models. Notably, modifications significantly improved dispersibility f-Gd@C82 NPs, thus substantially enhancing bioavailability. Moreover, NPs demonstrate excellent cytocompatibility various cell lines possess ability penetrate blood–brain barrier mice. Large-scale molecular dynamics simulations illuminate inhibition disaggregation mechanisms. Our design successfully overcomes limitations other nanocandidates, often overly rely hydrophobic interactions photothermal conversion properties, offers viable direction developing anti-AD agents through reversal aggregation.

Language: Английский

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Adenosine triphosphate induces amorphous aggregation of amyloid β by increasing Aβ dynamics

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: April 7, 2024

Abstract Amyloid β (Aβ) aggregates into two distinct fibril and amorphous forms in the brains of patients with Alzheimer’s disease. Adenosine triphosphate (ATP) is a biological hydrotrope that causes Aβ to form inhibit formation at physiological concentrations. Based on diffracted X-ray blinking (DXB) analysis, dynamics significantly increased immediately after ATP was added compared those absence presence ADP AMP, effect diminished 30 min as formed. In ATP, β-sheet content gradually from beginning, rapidly 180 incubation, revealed by time-dependent thioflavin T fluorescence assay. Images an atomic force microscope induces average diameter less than 100 nm, preventing fibrillar during 4 days incubation 37 °C. may induce aggregation increasing Aβ, result, other pathway omitted. Our results also suggest DXB analysis useful method evaluate inhibitory formation.

Language: Английский

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Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ42 Oligomers and Protect Synapses

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Jan. 30, 2020

Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought be a major contributor cognitive decline in Alzheimer's disease (AD). However, the exact role Aβ42 synaptotoxicity ability peripheral innate immune cells rescue synapses remain poorly understood metastable nature oligomers. Here, we utilized photo-induced cross-linking stabilize pure study their effects versus fibrils on protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity spike waveform), loss VGluT1- PSD95-excitatory synapses. Co-culturing with bone marrow-derived macrophages protected against fibrils; moreover, activation glatiramer acetate (GA) conferred further Mechanisms involved increased removal macrophages, amplified GA stimulation: largely cleared through intracellular CD36/EEA1+-early endosomal proteolysis, while primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies GA-immunized or CD115+-monocyte-grafted APPSWE/PS1ΔE9-transgenic mice followed pre- postsynaptic analyses entorhinal cortex hippocampal substructures corroborated our vitro findings macrophage-mediated preservation. Together, data demonstrate activated effectively clear VGluT1/PSD95 synapses, providing rationale for harnessing treat AD.

Language: Английский

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Activation of STAT3 Regulates Reactive Astrogliosis and Neuronal Death Induced by AβO Neurotoxicity

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(20), P. 7458 - 7458

Published: Oct. 10, 2020

Amyloid-beta oligomers (AβO) have been proposed as the most potent neurotoxic and inflammation inducers in Alzheimer’s disease (AD). AβO contribute to AD pathogenesis by impairing production of several cytokines inflammation-related signaling pathways, such Janus kinases/signal transducer transcription factor-3 (JAK/STAT3) pathway. STAT3 modulates glial activation, indirectly regulates Aβ deposition, induces cognitive decline transgenic models. However, vivo studies using an microinjection rat model not yet explored role. The main purpose this study was elucidate if a single could promote increased expression cells favoring neuroinflammation neurodegeneration. We designed intrahippocampal assessed production, expression, neurodegeneration time. Our results showed robust (mainly astrocytes) neurons, correlating with neuronal death response administration. A inhibition assay conducted primary hippocampal cultures, suggested that induction factor astrocytes leads them activation state may favor death. Notwithstanding, pharmacological JAK2/STAT3 pathway should be focused on because it is also essential neurons survival. Overall, these findings strongly suggest participation development

Language: Английский

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Free Cholesterol Accelerates Aβ Self-Assembly on Membranes at Physiological Concentration

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(5), P. 2803 - 2803

Published: March 3, 2022

The effects of membranes on the early-stage aggregation amyloid β (Aβ) have come to light as potential mechanisms by which neurotoxic species are formed in Alzheimer's disease. We shown that direct Aβ-membrane interactions dramatically enhance Aβ aggregation, allowing for oligomer assembly at physiologically low concentrations monomer. Membrane composition is also a crucial factor this process. Our results showed apart from phospholipids composition, cholesterol significantly enhances kinetics. It has been reported free present plaques. Here we report cholesterol, along with its presence inside membrane, further accelerate process producing aggregates more rapidly and larger sizes. These aggregates, lipid bilayer, able dissociate surface accumulate bulk solution; accelerates dissociation well. All-atom molecular dynamics simulations show binds monomers changes conformational sampling monomer; than doubling fraction low-energy conformations compared those absence can contribute indicate Aβ-lipid interaction an important disease prone

Language: Английский

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First Insight into the Neuroprotective and Antibacterial Effects of Phlorotannins Isolated from the Cell Walls of Brown Algae Fucus vesiculosus and Pelvetia canaliculata

Antioxidants, Journal Year: 2023, Volume and Issue: 12(3), P. 696 - 696

Published: March 11, 2023

Phaeophyceae (brown algae) essentially contribute to biotopes of cold and temperate seas. Their thalli are rich in biologically active natural products, which strongly universally dominated with phlorotannins—polyphenols complex diverse structure based on multiple differently arranged phloroglucinol units well known as strong antioxidants a broad spectrum biological activities. In the algal cells, phlorotannins can either accumulate cytoplasm or be secreted into cell wall (CW). The activities extractable intracellular have been comprehensively characterized, whereas properties CW-bound polyphenol fraction still mostly unknown. Recently, we identified dibenzodioxin bonding principal structural feature fucoid algae, soluble rely aryl ether bonds. However, profiles activity associated these differences Therefore, best our knowledge, for first time address antioxidant, cytotoxic, neuroprotective, antibacterial phlorotannin fractions isolated from two representatives order Fucales—Fucus vesiculosus Pelvetia canaliculata. appeared softer antioxidants, stronger agents were featured less cytotoxicity comparison fraction. neuroprotective effects both sub-cellular F. P. canaliculata similar. Thus, due their lower cytotoxicity, considered promising neuroprotectors.

Language: Английский

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