Receptor modulated assembly and drug induced disassembly of amyloid beta aggregates at asymmetric neuronal model biomembranes

Biophysical Chemistry, Год журнала: 2025, Номер unknown, С. 107441 - 107441

Опубликована: Март 1, 2025

Amyloid peptide non-fibrillar oligomers cause neurotoxicity and may contribute to Alzheimer's disease (AD) pathogenesis. Mounting evidence indicates that Aβ1-42 disrupt remodel neuronal membrane, causing cell death. The involvement of individual membrane constituents in real-time aggregate assembly is unclear due complexity membrane. We used non-Faradaic electrochemical impedance spectroscopy (EIS) track monomeric binding aggregation pathways asymmetric micropore suspended lipid bilayer membranes with anionic phospholipids glycosphingolipids. Anionic DOPC:PIP2 pore showed pore-formation within 2 h incubation, but insertion occurred over 6 h, an onset time ∼6-8 for at the surface. Among different gangliosides, GM1- GM3-containing did not result development, receptor mediated formation caused admittance decrease h. In contrast, partial surface increases GD1a mixed GSL membranes, arresting aggregation. Time-lapsed AFM imaging solid supported bilayers (aSLBs) corroborated EIS findings, capturing routes. Fluorescence lifetime (FLIM) spatial resolved single-point fluorescence correlation (FCS) aSLBs revealed membrane-peptide interaction, assembly, induced reorganization. Treatment antidepressants fluoxetine imipramine therapeutics, synergy, which are cost-effective capable crossing central nervous system (CNS+), resulted disassembly aggregates, fibrils. Overall, data suggests membrane-mediated correct timing AD progression halt or reverse amyloid through use repurposed drugs.

Язык: Английский

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[18F]Mefway: Imaging Serotonin 5HT1A Receptors in Human Postmortem Alzheimer’s and Parkinson’s Disease Anterior Cingulate. Potential Applications to Human Positron Emission Tomography Studies

Biomolecules, Год журнала: 2025, Номер 15(4), С. 592 - 592

Опубликована: Апрель 16, 2025

Serotonin 5HT1A receptors may be affected in neurodegeneration, such as Alzheimer’s disease (AD) and Parkinson’s (PD). Using the selective receptor positron emission tomography (PET) imaging agent, [18F]mefway, autoradiographic studies from postmortem human brains of AD, PD, cognitively normal (CN) subjects were carried out. Levels [18F]mefway binding compared with monoamine oxidase A (MAO-A) measured using [18F]FAZIN3 dopamine D2/D3 [18F]fallypride same subjects. Autoradiograms brain sections anterior cingulate corpus callosum CN, AD (n = 6 each group) analyzed. Significant increased was found (+30%) PD (+11%) to CN brains. This increase positively correlated binding, suggesting greater availability when MAO-A levels are higher. Differences three groups not significant. Our results support finding that is elevated cortex negatively MAO-A. upregulation potentially a response lower serotonin due activity this region or other neuroinflammatory changes. Thus, potential target for diagnostic therapeutic approaches PD.

Язык: Английский

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The Contribution of the Locus Coeruleus–Noradrenaline System Degeneration during the Progression of Alzheimer’s Disease

Biology, Год журнала: 2022, Номер 11(12), С. 1822 - 1822

Опубликована: Дек. 14, 2022

Alzheimer's disease (AD), which is characterized by extracellular accumulation of amyloid-beta peptide and intracellular aggregation hyperphosphorylated tau, the most common form dementia. Memory loss, cognitive decline disorientation are ultimate consequences neuronal death, synapse loss neuroinflammation in AD. In general, there many brain regions affected but locus coeruleus (LC) one earliest indicators neurodegeneration Since LC main source noradrenaline (NA) brain, degeneration AD leads to decreased NA levels, causing increased neuroinflammation, enhanced amyloid tau burden, phagocytosis impairment cognition long-term synaptic plasticity. this review, we summarized current findings on coeruleus-noradrenaline system its dysfunction now recognized as an important contributor progression.

Язык: Английский

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Drugs targeting APOE4 that regulate beta‐amyloid aggregation in the brain: Therapeutic potential for Alzheimer's disease

Basic & Clinical Pharmacology & Toxicology, Год журнала: 2024, Номер 135(3), С. 237 - 249

Опубликована: Июль 17, 2024

Abstract Alzheimer's disease is characterized by progressive cognitive decline, and behavioural psychological symptoms of dementia are common. The APOE ε4 allele, a genetic risk factor, significantly increases susceptibility to the disease. Despite efforts effectively treat disease, only seven drugs approved for its treatment, two these prevent progression. This highlights need identify new pharmacological options. review focuses on mimetic peptides, small molecule correctors HAE‐4 antibodies that target ApoE. These reduce β‐amyloid‐induced neurodegeneration in preclinical models. In addition, loop diuretics such as bumetanide furosemide show potential prevalence humans, antidepressants imipramine improve function individuals diagnosed with Consistent this, both classes have been shown exert neuroprotective effects inhibiting ApoE4‐catalysed Aβ aggregation Moreover, peroxisome proliferator‐activated receptor ligands, particularly pioglitazone rosiglitazone, ApoE4‐induced animal However, they do not decline allele carriers. Finally, ApoE4 impairs integrity blood–brain barrier haemostasis. On this basis, modulation promising avenue treatment late‐onset

Язык: Английский

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Cell Model of Depression: Reduction of Cell Stress with Mirtazapine

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(9), С. 4942 - 4942

Опубликована: Апрель 29, 2022

Depression is a very prevalent and complex disease. This condition associated with high rate of relapse, making its treatment challenge. Thus, an intensive investigation this disease necessary. In work, through cell viability assays (MTT neutral red assays) alkaline comet assays, we aimed to test the induction stress in human SH-SY5Y cells application hydrocortisone hydrogen peroxide reversal or attenuation mirtazapine cells. Our results demonstrated that peroxide, not hydrocortisone, can induce cellular stress, as evidenced by DNA damage global reduction, which were alleviated antidepressant mirtazapine. The establishment model depression important study new possibilities using cultures.

Язык: Английский

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Pathogenesis of miR-155 on nonmodifiable and modifiable risk factors in Alzheimer’s disease

Alzheimer s Research & Therapy, Год журнала: 2023, Номер 15(1)

Опубликована: Июль 14, 2023

Abstract Alzheimer’s disease (AD) is a common age-related neurodegenerative in the central nervous system and primary cause of dementia. It clinically characterized by memory impairment, aphasia, apraxia, agnosia, visuospatial executive dysfunction, behavioral changes, so on. Incidence this was bound up with age, genetic factors, cardiovascular cerebrovascular other basic diseases, but exact etiology has not been clarified. MicroRNAs (miRNAs) are small endogenous non-coding RNAs that were involved regulation post-transcriptional gene expression. miRNAs have extensively studied as noninvasive potential biomarkers for due to their relative stability bodily fluids. In addition, they play significant role physiological pathological processes various neurological disorders, including stroke, AD, Parkinson’s disease. MiR-155, an important pro-inflammatory mediator neuroinflammation, reported participate progression β-amyloid peptide tau via regulating immunity inflammation. review, we put emphasis on effects miR-155 AD explore underlying biological mechanisms which could provide novel approach diagnosis treatment AD.

Язык: Английский

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Clinical relevance of biomarkers, new therapeutic approaches, and role of post-translational modifications in the pathogenesis of Alzheimer’s disease

Frontiers in Aging Neuroscience, Год журнала: 2022, Номер 14

Опубликована: Сен. 7, 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes progressive loss of cognitive functions like thinking, memory, reasoning, behavioral abilities, and social skills thus affecting the ability person to perform normal daily independently. There no definitive cure for this disease, treatment options available management are not very effective as well. Based on histopathology, AD characterized by accumulation insoluble deposits amyloid beta (Aβ) plaques neurofibrillary tangles (NFTs). Although several molecular events contribute formation these deposits, aberrant post-translational modifications (PTMs) AD-related proteins (like APP, Aβ, tau, BACE1) also known be involved in onset progression disease. However, early diagnosis well development therapeutic approaches impeded lack proper clinical biomarkers. In review, we summarized current status relevance biomarkers from cerebrospinal fluid (CSF), blood extracellular vesicles AD. Moreover, highlight effects PTMs proteins, provide an insight how impact structure function leading pathology. Finally, disease-modifying therapeutics, novel approaches, targets discussed successful

Язык: Английский

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Addressing depression in older adults with Alzheimer’s through cognitive behavioral therapy: systematic review and meta-analysis

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Сен. 13, 2023

This systematic review and meta-analysis was conducted to provide an analysis of the published data about effects cognitive behavioral therapies on depression older adults with a diagnosis Alzheimer's disease.This study performed following PRISMA 2020 guidelines. The search between March April 2023, using four electronic databases: PubMed, Web Science, Cinhal Scopus. Different keywords combined Boolean operators were utilized. Only 11 articles included out initial 212.Cognitive therapy found reduce in individuals Alzheimer's, including treatments low frequency but longer intervention time.This that psychosocial is effective improving Alzheimer's. However, results are inconclusive due disparity findings heterogeneity applied protocols, so more studies needed this topic.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=416396, CRD42023416396.

Язык: Английский

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Significant Differences in the Reversal of Cellular Stress Induced by Hydrogen Peroxide and Corticosterone by the Application of Mirtazapine or L-Tryptophan

International Journal of Translational Medicine, Год журнала: 2022, Номер 2(3), С. 482 - 505

Опубликована: Сен. 3, 2022

Depression is a prevalent and debilitating disease worldwide. This pathology very complex the lack of efficient therapeutic modalities, as well high rates relapse, makes study treatment depression global healthcare challenge. Thus, an intense investigation this crucial urgent. In study, we focused on hydrogen peroxide corticosterone-induced stress SH-SY5Y HT-22 cells. Additionally, aimed to potential attenuation these induced with exposure both cells mirtazapine L-tryptophan, focusing cell viability assays (MTT Neutral Red) reactive oxygen species production (DCFDA fluorescence). Taken together, our results indicate that L-tryptophan counteract cellular by but not corticosterone, revealing role agents oxidative relief, highlighting serotonergic pathways in present depressed individuals. allows using models, enabling screening compounds may have be used acting mechanisms such protection.

Язык: Английский

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Combination of antidepressants and antipsychotics as a novel treatment option for psychosis in Alzheimer's disease

CPT Pharmacometrics & Systems Pharmacology, Год журнала: 2023, Номер 12(8), С. 1119 - 1131

Опубликована: Май 2, 2023

Abstract Psychotic symptoms are reported as one of the most common complications Alzheimer's disease (AD), in whom they associated with more rapid deterioration and increased mortality. Empiric treatments, namely first second‐generation antipsychotics, confer modest efficacy patients AD psychosis (AD+P) themselves increase Recent studies suggested use beneficial effects antidepressants among AD+P. This motivates our rationale for exploring their potential a novel combination therapy option these patients. We included electronic medical records 10,260 study. Survival analysis was performed to assess antipsychotics on mortality A protein–protein interaction network representing AD+P built, methods were used quantify drugs combined score developed measure synergetic effect against Our survival analyses showed that co‐administration have significant reducing targets well‐separated, similar Signed Jaccard Index (SJI) scores Eight drug pairs, including some popular recommendations like aripiprazole/sertraline, higher than average which suggest treating via strong effects. proposed combinations antipsychotic antidepressant superiority over current treatment The observed can be further strengthened by optimizing drug‐pair selection based systems pharmacology analysis.

Язык: Английский

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