Understanding of Alzheimer's Disease Pathophysiology for Therapeutic Implications of Natural Products as Neuroprotective Agents

Ageing Research Reviews, Год журнала: 2025, Номер unknown, С. 102680 - 102680

Опубликована: Фев. 1, 2025

Язык: Английский

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Inhibition of an Alzheimer’s disease–associated form of necroptosis rescues neuronal death in mouse models

Science Translational Medicine, Год журнала: 2024, Номер 16(771)

Опубликована: Окт. 30, 2024

Necroptosis is a regulated form of cell death that has been observed in Alzheimer’s disease (AD) along with the classical pathological hallmark lesions amyloid plaques and Tau neurofibrillary tangles. To understand neurodegenerative process AD, we studied role necroptosis mouse models primary neurons. Using immunohistochemistry, demonstrated activated necroptosis-related proteins transgenic mice developing pathology neurons from precursor protein (APP)–Tau double treated phosphorylated seeds derived patient AD but not APP only exhibited β-amyloid deposits. granulovacuolar degeneration (GVD) bodies were associated neuronal loss brain regions also known to be vulnerable GVD human brain. inhibitors lowered percentage showing reduced loss, both This suggests GVD-associated refer as “GVD-necroptosis” may represent delayed AD. We propose inhibition could rescue this type

Язык: Английский

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Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 21, 2024

Abstract Accumulation of pathological tau isoforms, especially hyperphosphorylated at serine 396 (pS396-tau) and oligomers, has been demonstrated in the retinas patients with mild cognitive impairment (MCI) Alzheimer’s disease (AD). Previous studies have noted a decrease retinal ganglion cells (RGCs) AD patients, but presence impact isoforms RGCs RGC integrity, particularly early stages, not explored. To investigate this, we examined superior temporal cross-sections from 25 MCI (due to AD) or dementia 16 cognitively normal (CN) controls, matched for age gender. We utilized marker ribonucleic acid binding protein multiple splicing (RBPMS) Nissl staining assess neuronal density cell layer (GCL). Our study found that hypertrophic containing pS396-tau T22-positive oligomers were more frequently observed compared CN subjects. Quantitative analyses indicated decline 46-55% 55-56% reductions RBPMS + (P<0.01) GCL neurons (P<0.01-0.001), respectively, patients. This count was accompanied by increases necroptotic-like morphology cleaved caspase-3 apoptotic Furthermore, there 2.1 3.1-fold increase (P<0.05-0.0001) pS396-tau-laden greater abundance individuals higher Braak stages (V-VI), severe clinical ratings (CDR=3), lower mini-mental state examination (MMSE) scores. Strong correlations between total amount RGCs, counts correlating significantly brain neurofibrillary tangle scores ( r = 0.71, P= 0.0001), stage 0.65, 0.0009), MMSE -0.76, 0.0004). These findings suggest tauopathy, characterized oligomeric is associated may contribute degeneration AD. Future research should validate these larger cohorts explore noninvasive imaging techniques target pathology improve detection monitor progression.

Язык: Английский

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Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer’s disease

Acta Neuropathologica Communications, Год журнала: 2025, Номер 13(1)

Опубликована: Фев. 15, 2025

Abstract Pathological tau isoforms, including hyperphosphorylated at serine 396 (pS396-tau) and oligomers (Oligo-tau), are elevated in the retinas of patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) AD dementia. These exhibit significant retinal ganglion cell (RGC) loss, however presence isoforms RGCs their impact on RGC integrity, particularly early AD, have not been studied. Here, we analyzed superior temporal cross-sections from 25 MCI or 16 age- sex-matched cognitively normal controls. Using marker ribonucleic acid binding protein multiple splicing (RBPMS) Nissl staining, found a 46–56% reduction RBPMS + neurons layer (GCL) ( P < 0.05–0.001). loss was accompanied by soma hypertrophy (10–50% enlargement, 0.05–0.0001), nuclear displacement, apoptosis (30–50% increase, 0.05–0.01), prominent expression granulovacuolar degeneration (GVD) bodies GVD-necroptotic markers. Both pS396-tau Oligo-tau were identified RGCs, hypertrophic cells. PS396-tau counts significantly increased 2.1–3.5-fold versus control 0.05–0.0001). Tauopathy-laden strongly inter-correlated r =0.85, 0.0001) tauopathy associated =-0.40–(-0.64), 0.05–0.01). Their abundance correlated brain pathology deficits, higher tauopathy-laden Braak stages (V–VI), clinical dementia ratings (CDR = 3), mini-mental state examination (MMSE ≤ 26) scores. central mid-periphery showed closest associations status, while exhibited strongest correlations (NFTs, stages, ABC scores; S =0.78–0.81, 0.001–0.0001) decline (MMSE; =-0.79, 0.0019). Overall, these findings identify link between pathogenic involving apoptotic death pathways. Future research should validate results larger more diverse cohorts develop as potential noninvasive biomarker for detection monitoring progression.

Язык: Английский

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Identification of a novel pyrrolo[2,3- b ]pyridine compound as a potent glycogen synthase kinase 3β inhibitor for treating Alzheimer’s disease

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2025, Номер 40(1)

Опубликована: Фев. 20, 2025

Herein, a novel pyrrolo[2,3-b]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, S01, was rationally designed and synthesised to target Alzheimer's disease (AD). S01 inhibited GSK-3β, with an IC50 of 0.35 ± 0.06 nM, had acceptable selectivity for 24 structurally similar kinases. Western blotting assays indicated that efficiently increased the expression p-GSK-3β-Ser9 decreased p-tau-Ser396 levels in dose‐dependent manner. In vitro cell experiments, showed low cytotoxicity SH-SY5Y cells, significantly upregulated β-catenin neurogenesis-related biomarkers, effectively promoted outgrowth differentiated neuronal neurites. Moreover, substantially ameliorated dyskinesia AlCl3-induced zebrafish AD models at concentration 0.12 μM, which more potent than Donepezil (8 μM) under identical conditions. Acute toxicity experiments further confirmed safety vivo. Our findings suggested is prospective GSK-3β inhibitor can be tested as candidate treating AD.

Язык: Английский

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Necroptosis, Autophagy and Parthanatos in the Pathogenesis of Brain Diseases

Journal of Evolutionary Biochemistry and Physiology, Год журнала: 2025, Номер 61(2), С. 486 - 513

Опубликована: Март 1, 2025

Язык: Английский

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Different Forms of Regulated Cell Death in Type-2-Diabetes-Mellitus-Related Osteoporosis: A Focus on Mechanisms and Therapeutic Strategies

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(9), С. 4417 - 4417

Опубликована: Май 6, 2025

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with high prevalence and challenging treatment options. It significantly affects the function of various organs, including bones, imposes substantial social economic costs. Chronic hyperglycemia, insulin resistance, abnormalities in glucolipid metabolism can lead to cellular damage within body. Bone dysfunction represents significant characteristic diabetic osteoporosis (DOP). Recent studies confirm that cell death critical factor contributing bone damage. Regulated (RCD) highly controlled process involves numerous proteins specific signaling cascades. RCD processes, apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, cuproptosis, may be linked cells T2DM. In this review, types populations during pathogenic DOP were explored, link between processes pathogenesis was further explored. addition, research progress on targeting for summarized paper. This provide foundation additional explorations drug development, as well new therapeutic concepts clinical management DOP.

Язык: Английский

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The Interplay Between Accumulation of Amyloid-Beta and Tau Proteins, PANoptosis, and Inflammation in Alzheimer’s Disease

NeuroMolecular Medicine, Год журнала: 2024, Номер 27(1)

Опубликована: Дек. 29, 2024

Язык: Английский

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Neuroprotective Potential of Indole-Based Compounds: A Biochemical Study on Antioxidant Properties and Amyloid Disaggregation in Neuroblastoma Cells

Antioxidants, Год журнала: 2024, Номер 13(12), С. 1585 - 1585

Опубликована: Дек. 23, 2024

Based on the established neuroprotective properties of indole-based compounds and their significant potential as multi-targeted therapeutic agents, a series synthetic indole–phenolic was evaluated multifunctional neuroprotectors. Each compound demonstrated metal-chelating properties, particularly in sequestering copper ions, with quantitative analysis revealing approximately 40% chelating activity across all compounds. In cellular models, these hybrid exhibited strong antioxidant cytoprotective effects, countering reactive oxygen species (ROS) generated by Aβ(25–35) peptide its oxidative byproduct, hydrogen peroxide, showing average 25% increase cell viability reduction ROS levels to basal states. Further using thioflavin T fluorescence assays, circular dichroism, computational studies indicated that synthesized derivatives effectively promoted self-disaggregation fragment. Taken together, findings suggest unique profile actions for derivatives, combining chelating, antioxidant, anti-aggregation which position them promising development agents Alzheimer’s disease therapy. The methods used provide reliable vitro data, although further vivo validation assessment blood–brain barrier penetration are needed confirm efficacy safety.

Язык: Английский

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Detection of Brain-Derived Cell-Free DNA in Plasma

Diagnostics, Год журнала: 2024, Номер 14(22), С. 2541 - 2541

Опубликована: Ноя. 13, 2024

Background: Neuronal loss is a major pathological feature of neurodegenerative diseases. The analysis plasma cell-free DNA (cfDNA) an emerging approach to track cell death events in minimally invasive way and from inaccessible areas the body, such as brain. Previous studies showed that methylation (DNAm) profiles can be used map tissue origin cfDNA identify molecules released brain upon death. aim present study contribute this research field, presenting development validation assay for detection brain-derived (bcfDNA). Methods: To CpG sites with brain-specific DNAm, we compared non-brain tissues their chromatin state genome-wide DNAm data, available public datasets. selected target genomic regions were experimentally validated by bisulfite sequencing on extracted 44 different autoptic tissues, including multiple regions. Sequencing data analysed epihaplotypes. developed was tested patients immune effector cell-associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor T (CAR-T) therapy. Results: We five (four hypomethylated one hypermethylated brain). samples CAR-T revealed higher levels bcfDNA participants ongoing syndrome. Conclusions: plasma. promising tool early neuronal

Язык: Английский

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