Structural polymorphism and cytotoxicity of brain‐derived β‐amyloid extracts

Protein Science, Journal Year: 2023, Volume and Issue: 32(5)

Published: April 13, 2023

To date, more than 37 amyloidogenic proteins have been found to form toxic aggregates that are implicated in the progression of numerous debilitating protein misfolding diseases including Alzheimer's disease (AD). Extensive literature highlights role β-amyloid (Aβ) causing excessive neuronal cell loss brains AD patients. In fact, major advances our understanding Aβ aggregation process, kinetics, toxicity, and structures fibrillar revealed by examining vitro preparations synthetic peptides. However, ongoing research shows brain-derived specific characteristics distinguish them from prepared species. Notably, molecular amyloid fibrils grown human brain were be markedly different fibrils. addition, recent findings report existence heterogeneous proteoforms tissue contrast synthetically produced full-length aggregates. Despite their high relevance progression, species less well-characterized compared with The aim this review is provide an overview on particular focus studies as well pathological roles progression. main motivation highlight importance utilizing amyloids for characterizing structural effects With knowledge, can adopted identify relevant drug targets validate potent inhibitors toward designing highly effective therapeutic strategies against AD.

Language: Английский

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Correlation between variants of the CREB1 and GRM7 genes and risk of depression

BMC Psychiatry, Journal Year: 2023, Volume and Issue: 23(1)

Published: Jan. 3, 2023

Abstract The pathogenesis of depression involves cAMP -response element binding protein1 ( CREB1 ) and metabotropic glutamate receptor 7 GRM7 ), their genetic polymorphisms may affect susceptibility to depression. purpose this study was investigate whether the rs2253206 rs10932201 polymorphism rs162209 are associated with risk Using polymerase chain reaction-restriction fragment length DNA sequencing, we analyzed , rs10932201, frequencies in 479 patients 329 normal controls. results showed that were significantly an increased However, no association found between risk. When data stratified for several disease-related variables, none three be correlated onset, disease severity, family history, or suicidal tendency. Thus, present findings indicate related occurrence

Language: Английский

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Mechanobiological insight into brain diseases based on mechanosensitive channels: Common mechanisms and clinical potential

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(6)

Published: June 1, 2024

Abstract Background As physical signals, mechanical cues regulate the neural cells in brain. The mechanosensitive channels (MSCs) perceive and transduce them by permeating specific ions or molecules across plasma membrane, finally trigger a series of intracellular bioelectrical biochemical signals. Emerging evidence supports that wide‐distributed, high‐expressed MSCs like Piezo1 play important roles several neurophysiological processes neurological disorders. Aim s To systematically conclude functions brain provide novel mechanobiological perspective for diseases. Method We summarized detected research progress on functional physiological conditions. then concluded pathological activation downstream pathways triggered two categories diseases, neurodegenerative diseases place‐occupying damages. Finally, we outlined methods manipulating discussed their medical potential with some crucial outstanding issues. Results present underlying common mechanisms different acting as “transportation hubs” to distinct signal patterns: upstream pathways. Manipulating is feasible alter complicated processes, providing promising targets clinical treatment. Conclusions Recent provides insight into mediated inspire wide range therapeutic potentials targeted

Language: Английский

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Insight into brain metallothioneins from bidirectional Zn2+ signaling in synaptic dynamics

Metallomics, Journal Year: 2024, Volume and Issue: 16(9)

Published: Sept. 1, 2024

The basal levels as the labile Zn2+ pools in extracellular and intracellular compartments are range of ∼10 nM ∼100 pM, respectively. influx is used for memory via cognitive activity regulated synaptic plasticity, a cellular mechanism memory. When into neurons excessively occurs, however, it becomes critical trigger decline neurodegeneration, resulting acute chronic pathogenesis. Aging, biological process, generally accelerates vulnerability to neurodegenerative disorders such Alzheimer's disease (AD) Parkinson's (PD). level age relatedly increased rat hippocampus, contributes accelerating AD PD pathogenesis experimental animals with aging. Metallothioneins (MTs) Zn2+-binding proteins homeostasis involved not only supplying functional required activity, but also capturing excess (toxic) neurodegeneration. Therefore, estimated that regulation MT synthesis both neuronal neuroprotection. present report provides recent knowledge regarding protective/preventive potential against normal aging animals, focused on function bidirectional signaling dynamics.

Language: Английский

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Targets and mechanisms of Alpinia oxyphylla Miquel fruits in treating neurodegenerative dementia

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: Nov. 30, 2022

The dried and ripe fruits of Alpinia oxyphylla Miquel (AO) have the effects tonifying kidney-essence nourishing intelligence thus been widely used in treating dementia. Alzheimer's disease (AD) is a typical form neurodegenerative dementia with deficiency Traditional Chinese Medicine (TCM). So far, there lack systematic studies on biological basis corresponding phytochemicals. In this study, we investigated targets AO based key pathophysiological processes According to ultra-high-performance liquid chromatography triple quadrupole mass spectrometry data Lipinski's rule five, 49 bioactive phytochemicals from were identified, 26 them found target 168 molecules treatment Nine shown acetylcholinesterase (ACHE), 19 butyrylcholinesterase (BCHE). A database involving 731 genes was constructed. Furthermore, yakuchinone B, 5-hydroxy-1,7-bis (4-hydroxy-3-methoxyphenyl) heptan-3-one (5-HYD), oxyhylladiketone, oxyphyllacinol, butyl-β-D-fructopyranoside, dibutyl phthalate, chrysin, A, rhamnetin, rhamnocitrin identified as that regulate pathogenesis multitargeted manner. approach studying pharmacological mechanism underlying medicinal plants TCM syndrome may be helpful translation TCM.

Language: Английский

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Protective effect of glutamic-oxaloacetic transaminase on hippocampal neurons in Alzheimer's disease using model mice

Neuroscience Letters, Journal Year: 2023, Volume and Issue: 803, P. 137194 - 137194

Published: March 16, 2023

Alzheimer's disease (AD), a neurodegenerative affecting the elderly, frequently causes cognitive impairment and memory decline, there are currently no effective therapeutic drugs available. Glutamate excitotoxicity is one of pathogeneses AD, evidence that glutamic-oxaloacetic transaminase (GOT) can significantly reduce glutamate concentrations in hippocampi mice, but its role APP/PS1 transgenic mice unknown. We investigated improvement neurological function related protein expression following subcutaneous injection GOT with AD. performed immunohistochemical staining on brain tissue 3-, 6-, 12-month-old found content β-amyloid Aβ1-42 6 months old treatment group was reduced. Meanwhile, APP-GOT outperformed APP water maze spatial object recognition experiments. The number neurons hippocampal CA1 area increased when compared to according Nissl staining. Electron microscopic examination demonstrated synapses more than group, mitochondrial structure relatively complete. Finally, hippocampus detected. In comparison SIRT1 whereas decreased, Ex527 could reverse this trend. These results suggest improve early stage underlying mechanism may be through decreasing increasing expressions.

Language: Английский

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Tau and Amyloid β Protein in Patient-Derived Aqueous Brain Extracts Act Concomitantly to Disrupt Long-Term Potentiationin Vivo

Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 43(32), P. 5870 - 5879

Published: July 25, 2023

Amyloid β protein (Aβ) and tau, the two main proteins implicated in causing Alzheimer's disease (AD), are posited to trigger synaptic dysfunction long before significant loss occurs vulnerable circuits. Whereas soluble Aβ aggregates from AD brain well recognized potent synaptotoxins, less is known about synaptotoxicity of tau or other tauopathy patient brains. Minimally manipulated patient-derived aqueous extracts contain more diffusible native forms these proteins. Here, we explore how intracerebral injection present such contribute disruption plasticity CA1 area male rat hippocampus. Aqueous certain brains acutely inhibited long-term potentiation (LTP) transmission a manner that required both tau. Tau-containing with Pick's (PiD) also impaired LTP, either PiD lowered threshold for inhibit LTP. Remarkably, LTP persisted at least 2 weeks after single injection. These findings support critical role rapid onset, persistent deficits, promoting Aβ-mediated dysfunction.

Language: Английский

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Targeting epigenetic mechanisms in amyloid-β–mediated Alzheimer’s pathophysiology: unveiling therapeutic potential

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(1), P. 54 - 66

Published: March 1, 2024

Alzheimer's disease is a prominent chronic neurodegenerative condition characterized by gradual decline in memory leading to dementia. Growing evidence suggests that associated with accumulating various amyloid-β oligomers the brain, influenced complex genetic and environmental factors. The cognitive deficits observed during prodromal mild impairment phases of are believed primarily result from synaptic dysfunction. Throughout life, factors can lead enduring changes gene expression emergence brain disorders. These changes, known as epigenetic modifications, also play crucial role regulating formation synapses their adaptability response neuronal activity. In this context, we highlight recent advances understanding roles played key components machinery, specifically DNA methylation, histone modification, microRNAs, development disease, function, activity-dependent plasticity. Moreover, explore strategies, including enriched environments, exposure non-invasive stimulation, use pharmacological agents, aimed at improving function enhancing long-term potentiation, process integral mechanisms. Lastly, deliberate on effective agents safe therapeutic approaches for managing disease. We suggest addressing may require distinct tailored drugs targeting different stages or pathways rather than relying single drug.

Language: Английский

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Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology, cognition, and behavior in APP/PS1 mice

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(2), P. 533 - 547

Published: April 16, 2024

JOURNAL/nrgr/04.03/01300535-202502000-00030/figure1/v/2024-05-28T214302Z/r/image-tiff In patients with Alzheimer's disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 development disease remains unclear. This study aimed explore effect on cognitive function and brain pathology an APP/PS1 mouse model as well underlying mechanism. We a significant reduction two vitro models (Aβ1-42-treated hCMEC/D3 bEnd.3 cells), model. Additionally, injection mice adeno-associated virus encoding enhanced hippocampal synaptic plasticity mitigated deficits. Interestingly, increasing cells reduced levels both soluble insoluble amyloid-β brains mice. may attributable inhibition β-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that inversely associated pathogenesis, upregulation mitigates deficits These suggest potential therapeutic target biomarker for disease.

Language: Английский

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Rapidly reversible persistent long-term potentiation inhibition by patient-derived brain tau and amyloid ß proteins

Philosophical Transactions of the Royal Society B Biological Sciences, Journal Year: 2024, Volume and Issue: 379(1906)

Published: June 10, 2024

How the two pathognomonic proteins of Alzheimer's disease (AD); amyloid ß (Aß) and tau, cause synaptic failure remains enigmatic. Certain synthetic recombinant forms these are known to act concurrently acutely inhibit long-term potentiation (LTP). Here, we examined effect early amyloidosis on acute disruptive action synaptotoxic tau prepared from protein in patient-derived aqueous brain extracts. We also explored persistence inhibition LTP by different preparations. A single intracerebral injection aggregates human that had been either sonication fibrils (SτAs) or disulfide bond formation (oTau) rapidly persistently inhibited rat hippocampus. The threshold for inhibitory oTau was lowered precursor (APP)-transgenic rats. tau-containing AD Pick's extracts LTP, over weeks. Remarkably, persistent disruption plasticity reversed a anti-tau monoclonal antibodies, including one directed specific amino acid sequence. conclude LTP-disrupting species persist weeks, maintaining their neuroactivity often concert with Aß. This article is part discussion meeting issue 'Long-term potentiation: 50 years on'.

Language: Английский

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