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

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

Language: 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, Journal Year: 2025, Volume and Issue: 13(3), P. 178 - 178

Published: Feb. 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.

Language: 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, Journal Year: 2025, Volume and Issue: 31(4)

Published: April 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 .

Language: 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, Journal Year: 2025, Volume and Issue: 26(8), P. 3756 - 3756

Published: April 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.

Language: Английский

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BIN1 and Alzheimer’s disease: the tau connection

Trends in Neurosciences, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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

Nutrients, Journal Year: 2024, Volume and Issue: 16(23), P. 4171 - 4171

Published: Nov. 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

Language: Английский

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Regulated cell death in neurodegeneration: pathways and therapeutic horizons

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Sept. 24, 2024

Language: Английский

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Editorial: The (un)desirability of cell death in health and disease: emerging modulators and their mechanisms

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: Nov. 19, 2024

Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal. *Correspondence: Patrícia M. A. Silva ([email protected])The balanced regulation of cell death and survival is critical for maintaining the homeostasis human body. Disruption this delicate equilibrium often underlies development several diseases. For instance, cancer cells develop resistance to natural mechanisms, leading uncontrolled proliferation malignant growth (1,2). Conversely, neurodegenerative diseases involve progressive loss specific brain populations, resulting in a broad spectrum debilitating symptoms and, ultimately, (3, 4) (Figure 1).The incidence prevalence both are rising rapidly, significantly impacting patients' quality life creating major economic healthcare challenges worldwide (5,6). While knowledge about role abnormal these has advanced, precise mechanisms driving processes, as well effective strategies modulate them, remain only partially understood. This limited understanding complicates efforts tailor treatments different disease types. cancer, therapeutic approaches focus on inducing eliminate cells, whereas diseases, goal shifts preventing preserve affected neurons delay symptom progression. Research Topic focused enriching our emerging modulators death, exploring their action potential applications various scenarios.In total, two original research articles three review were published. editorial briefly summarizes findings highlights key insights derived from articles, emphasizing contributions field they present guiding future and/or strategies. release ALL dependent Gαi subunit, its inhibition blocks process without affecting Gβϒ. Moreover, further experiments showed that activating adenylyl cyclase (AC) with forskolin or using 8-CPT-cAMP inhibits D,L-methadone-induced ER Ca 2+ release, suggesting Gαi-mediated downregulation AC cAMP. Notably, protein kinase A (PKA) inhibitor 14-22 amide (myr) can independently elicit

Language: Английский

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The Critical Role of Autophagy and Phagocytosis in the Aging Brain

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 26(1), P. 57 - 57

Published: Dec. 25, 2024

As the organism ages, there is a decline in effective energy supply, and this retards ability to elaborate new proteins. The consequences of are especially marked gradual brain function. senescence cells their constituent organelles ultimately cause aging entire nervous system. What less immediately obvious that also accompanied by failure catabolic events lead removal non-functional ineffective subcellular components. non-working cellular elements within essential order allow appearance fresh with full range capacities. Thus, maintenance operative mechanisms for dispersal failed tissue components important, its diminished capacity significant contributory factor onset progression age-related neurological disorder. This report discusses underlying autophagy phagocytosis how these can be adversely modulated as proceeds. means which recycling may reinstated aged considered.

Language: Английский

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