Microglial NLRP3 Inflammasomes in Alzheimer’s Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics

Molecular Neurobiology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

Язык: Английский

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4-Hydroxynonenal from Mitochondrial and Dietary Sources Causes Lysosomal Cell Death for Lifestyle-Related Diseases

Nutrients, Год журнала: 2024, Номер 16(23), С. 4171 - 4171

Опубликована: Ноя. 30, 2024

Excessive consumption of vegetable oils such as soybean and canolla containing ω-6 polyunsaturated fatty acids is considered one the most important epidemiological factors leading to progression lifestyle-related diseases. However, underlying mechanism vegetable-oil-induced organ damage incompletely elucidated. Since proopiomelanocortin (POMC) neurons in hypothalamus are related control appetite energy expenditure, their cell degeneration/death crucial for occurrence obesity. In patients with metabolic syndrome, saturated acids, especially palmitate, used an source. abundant reactive oxygen species produced during β-oxidation palmitate mitochondria, increased amount 4-hydroxy-2-nonenal (4-HNE) endogenously generated from linoleic constituting cardiolipin inner membranes. Further, due daily intake deep-fried foods and/or high-fat diets cooked using oils, exogenous 4-HNE being via lipid peroxidation heating incorporated into blood. By binding atheromatous senile plaques, inactivates proteins forming hybrid covalent chemical addition compounds causes cellular dysfunction tissue by specific oxidation carbonylation. overstimulates G-protein-coupled receptors induce abnormal Ca

Язык: Английский

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Alzheimer’s, Parkinson’s, Frontotemporal Lobar Degeneration, and Amyotrophic Lateral Sclerosis Start in Pediatric Ages: Ultrafine Particulate Matter and Industrial Nanoparticles Are Key in the Early-Onset Neurodegeneration: Time to Invest in Preventive Medicine

Toxics, Год журнала: 2025, Номер 13(3), С. 178 - 178

Опубликована: Фев. 28, 2025

Billions of people are exposed to fine particulate matter (PM2.5) levels above the USEPA’s annual standard 9 μg/m3. Common emission sources anthropogenic, producing complex aerosolized toxins. Ultrafine (UFPM) and industrial nanoparticles (NPs) have major detrimental effects on brain, but USA does not measure UFPM a routine basis. This review focuses development progression common neurodegenerative diseases, as diagnosed through neuropathology, among young residents in Metropolitan Mexico City (MMC). MMC is one most polluted megacities world, with population 22 million residents, many whom unaware brain caused by their atmosphere. Fatal diseases (such Alzheimer’s Parkinson’s) that begin childhood populations living air environments preventable. We conclude UFPM/NPs capable disrupting neural homeostasis give rise relentless processes throughout entire life highly MMC. The paradigm reaching old age neurodegeneration no longer supported. Neurodegenerative changes start early pediatric ages irreversible. It time invest preventive medicine.

Язык: Английский

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Sanshen San Formula Hinders Cognitive Function and Pathology in Alzheimer's Disease Through Potentiating the Function of Synapse

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(4)

Опубликована: Апрель 1, 2025

ABSTRACT Background Alzheimer's disease ( AD ) constitutes a devastating neurodegenerative disorder, manifested by amyloid‐β aggregation, phosphorylated tau accumulation, and progressive cognitive deterioration. Current therapeutic interventions remain predominantly symptomatic, underscoring the urgency for more efficacious treatment strategies. Purpose This study elucidated potential of Sanshen San (SSS), traditional Chinese herbal formula encompassing Polygala Radix , Pini in Poria Acori Tatarinowii Rhizoma on function pathology. Methods We implemented both acute Aβ 1‐42 ‐injected mice 5xFAD transgenic mouse models. The efficacy SSS was assessed through behavioral paradigms including Y‐maze, Novel Object Recognition, Morris Water Maze. Molecular mechanisms were delineated utilizing RNA sequencing, metabolomics analysis, immunofluorescence staining, Golgi‐Cox transmission electron microscopy, Western blotting. Results Chemical analysis unveiled 10 principal bioactive compounds SSS. substantially ameliorated performance models, attenuated plaque burden, augmented microglial phagocytosis. safeguarded synaptic integrity, enhanced mitochondrial function, facilitated autophagy. Transcriptomic metabolomic analyses demonstrated that operates reinstating neurotransmitter particularly dopaminergic system. Conclusion efficaciously mitigates pathology potentiating optimizing homeostasis, restoring balance, exemplifying promising multi‐target strategy .

Язык: Английский

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Combination of Epigallocatechin-3-Gallate and Tramiprosate Prevent Accumulation of Intracellular Aβ and Dysfunctional Autophagy–Lysosomal Pathway at Earliest Stage of Transdifferentiation of Mesenchymal Stromal Cells into PSEN1 E280A Cholinergic-like Neurons

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(8), С. 3756 - 3756

Опубликована: Апрель 16, 2025

Familial Alzheimer’s disease (FAD) caused by presenilin 1 (PSEN1) E280A induces the aberrant accumulation of intracellular Aβ (iAβ) in cholinergic-like neurons (ChLNs). How early iAβ accumulates development ChLNs is still unknown. Consequently, timing appropriate therapeutic approaches against FAD unclear. To determine earliest PSEN1 ChLNs, flow cytometry and immunofluorescence microscopy were used to follow menstrual mesenchymal stromal cells (MenSCs) into (proliferation marker Ki67, cluster differentiation 73 (CD73), neuronal nuclei (NeuN) marker, choline acetyl transferase (ChAT)), kinetics accumulation, simultaneous evaluation other associated markers (e.g., DJ-1C106-SO3; lysosomes; phosphatidylethanolamine-conjugated microtubule-associated protein 1A/1B light chain 3, LC3-II; cleaved caspase 3 (CC3)) at 0, 1, 5, 7 days. reverse phenotype, we rapamycin (RAP), verubecestat (VER), compound E (CE), epigallocatechin-3-gallate (EGCG), tramiprosate (TM) WT mutant ChLNs. We found that did not induce significant differences NeuN ChAT MenSCs transitioning The cholinergic developmental stage from day 0 (18%, stage) (46%, stage), i.e., increased +156% compared (1–6%). A increase DJ-1C106-SO3 occurs only (+250%). While neither CC3 (0–1%) nor lysosomes different between any time point, a stepwise autophagosome was observed (15%) (79%), +427%, cells. RAP, VER, CE able completely reduce all E280A-induced combination EGCG TM more effective removing these than alone Given this investigation based on single blood sample E280A, our results should be considered exploratory. Larger sizes are needed.

Язык: Английский

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BIN1 and Alzheimer’s disease: the tau connection

Trends in Neurosciences, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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Dual Mechanism of Docosahexaenoic acid (DHA) in Alzheimer’s Disease: PAD4 Inhibition and Autophagy Stimulation

Molecular Neurobiology, Год журнала: 2025, Номер unknown

Опубликована: Май 2, 2025

Язык: Английский

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OTUD4 inhibits ferroptosis by stabilizing GPX4 and suppressing autophagic degradation to promote tumor progression

Cell Reports, Год журнала: 2025, Номер 44(5), С. 115681 - 115681

Опубликована: Май 1, 2025

Язык: Английский

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Trehalose Acts as a Mediator: Imbalance in Brain Proteostasis Induced by Polystyrene Nanoplastics via Gut Microbiota Dysbiosis during Early Life

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Май 13, 2025

As an emerging contaminant, nanoplastics have evolved into a global ecological issue. Studies shown that induce neurotoxicity across species, however, the causal mechanism remains unknown. This study aimed to explore underlying caused by polystyrene (PS-NPs) via microbiota-gut-brain axis in immature mice, which serve as model of infants and young children who are at higher exposure risk NPs. The results indicated while only minority PS-NPs reached brain after exposure, they still had significant neurotoxic effects, reflected abnormalities behavior, biochemical marker levels histopathology. Proteomics quantification analyses revealed proteostasis imbalance mediated lysosomal proteasome dysfunction is key reason for induced neurotoxicity. Further, we confirmed indirect role gut microbiota through 16S rDNA fecal transplantation. Crucial bacterial species such Eubacterium coprostanoligenes potentially act indicators dysbiosis exposure. Notably, first estimated effect on attributed mice 39.20% high-dimensional mediation analysis. Trehalose was identified mediator connecting brain, crucial trehalose supplementation highlighted remodeling alleviate mice. These findings expected contribute deeper understanding assessment health protection nervous system from early life.

Язык: Английский

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EphB receptors modulate neuropathic pain via Ca ²⁺ /calpain/autophagy in spinal cord of mice

Neurological Research, Год журнала: 2025, Номер unknown, С. 1 - 13

Опубликована: Май 23, 2025

The EphB receptors play an important role in regulation of neuropathic pain. This study aimed to investigate the spinal cord CCI mice. BACKGROUND: Previous studies have found that were upregulated bone cancer pain rats, and activation or inhibition regulated behaviors rats. However, specific mechanism involved is not clear. Normal mice injected with ephrinB2-Fc intrathecally activate receptors, changes behavior calpain activity detected. Intrathecal injection EphB2-Fc AAV-shEphB2 inhibits EphBs, mouse are Intraperitoneal inhibitor MDL-28170 was used detect effect ephrinB2 Fc on behavior. After inhibiting EphBs receptor mice, Ca2+- dependent p-ERK p-CaMKII, autophagy, inflammation related factors Spinal induced hyperalgesia normal while alleviated hypersensitivity by Fc. Inhibiting suppressed expression promoted reduced pro-inflammatory IL-6, IL-1 β, TNF - α, promotes IL-10 expression. In summary, regulate through neuroinflammation autophagy Ca2+/calpain/autophagy pathway.

Язык: Английский

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