Immune Activation in Alzheimer Disease

Annual Review of Immunology, Journal Year: 2024, Volume and Issue: 42(1), P. 585 - 613

Published: March 1, 2024

Alzheimer disease (AD) is the most common neurodegenerative disease, and with no efficient curative treatment available, its medical, social, economic burdens are expected to dramatically increase. AD historically characterized by amyloid β (Aβ) plaques tau neurofibrillary tangles, but over last 25 years chronic immune activation has been identified as an important factor contributing pathogenesis. In this article, we review recent advances in our understanding of significance development AD. We describe how brain-resident macrophages, microglia, able detect Aβ species be activated, well consequences activated microglia discuss transcriptional changes AD, their unique heterogeneity humans, emerging strategies study human microglia. Finally, expose, beyond role peripheral signals different cell types activation.

Language: Английский

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Blood–Brain Barrier-Targeting Nanoparticles: Biomaterial Properties and Biomedical Applications in Translational Neuroscience

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 612 - 612

Published: May 10, 2024

Overcoming the blood–brain barrier (BBB) remains a significant hurdle in effective drug delivery to brain. While BBB serves as crucial protective barrier, it poses challenges delivering therapeutic agents their intended targets within brain parenchyma. To enhance for treatment of neurological diseases, several technologies circumvent have been developed last few years. Among them, nanoparticles (NPs) are one most versatile and promising tools. Here, we summarize characteristics NPs that facilitate penetration, including size, shape, chemical composition, surface charge, importantly, conjugation with various biological or synthetic molecules such glucose, transferrin, insulin, polyethylene glycol, peptides, aptamers. Additionally, discuss coating surfactants. A comprehensive overview common vitro vivo models NP penetration studies is also provided. The discussion extends discussing impairment under pathological conditions leveraging alterations delivery. Emphasizing need future uncover inherent properties NPs, review advocates role beyond systems calls efforts translating clinic therapeutics. Overall, stand out highly strategy precise targeting disorders.

Language: Английский

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Therapeutic targeting of obesity-induced neuroinflammation and neurodegeneration

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 17, 2025

Obesity is a major modifiable risk factor leading to neuroinflammation and neurodegeneration. Excessive fat storage in obesity promotes the progressive infiltration of immune cells into adipose tissue, resulting release pro-inflammatory factors such as cytokines adipokines. These inflammatory mediators circulate through bloodstream, propagating inflammation both periphery central nervous system. Gut dysbiosis, which results leaky intestinal barrier, exacerbates plays significant role linking pathogenesis neurodegeneration gut-brain/gut-brain-liver axis. Inflammatory states within brain can lead insulin resistance, mitochondrial dysfunction, autolysosomal increased oxidative stress. disruptions impair normal neuronal function subsequently cognitive decline motor deficits, similar pathologies observed neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, Parkinson's disease. Understanding underlying disease mechanisms crucial for developing therapeutic strategies address defects these metabolic pathways. In this review, we summarize provide insights different strategies, methods alter gut lifestyle changes, dietary supplementation, well pharmacological agents derived from natural sources, that target obesity-induced

Language: Английский

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Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer’s Disease Therapeutics

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 279 - 279

Published: Jan. 23, 2025

Alzheimer’s disease (AD) is traditionally viewed through the lens of amyloid cascade hypothesis, implicating amyloid-beta and tau protein aggregates as main pathological culprits. However, burgeoning research points to brain’s resident immune cells, microglia, critical players in AD pathogenesis, progression, potential therapeutic interventions. This review examines dynamic roles microglia within intricate framework AD. We detail involvement these cells neuroinflammation, explaining how their activation response fluctuations may influence trajectory. further elucidate complex relationship between pathology. study highlights dual nature which contribute both aggregation clearance protein. Moreover, an in-depth analysis interplay unveils significant, yet often overlooked, impact this interaction on neurodegeneration Shifting from conventional approaches, we assess current treatments primarily targeting introduce novel strategies that involve manipulating microglial functions. These innovative methods herald a paradigm shift management Finally, explore field precision diagnosis pursuit robust biomarkers. underline more profound comprehension biology could enrich essential areas, potentially paving way for accurate diagnostic tools tailored treatment strategies. In conclusion, expands perspective pathology treatment, drawing attention multifaceted microglia. As continue enhance our understanding microglial-focused interventions emerge promising frontier bolster arsenal fight against

Language: Английский

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Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115204 - 115204

Published: Jan. 1, 2025

Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of monocytic lineage. Here, we examine how Neu1 influences microglia by modulating sialylation full-length Trem2 (Trem2-FL), a multifunctional receptor that microglial survival, phagocytosis, cytokine production. When is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, excessively cleaved into C-terminal fragment (Trem2-CTF) an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated (Sia-Trem2-FL) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampen NF-κB signaling, while sTrem2 propagates Akt-dependent cell survival NFAT1-mediated production TNF-α CCL3. Because are implicated neurodegenerative/neuroinflammatory diseases, including Alzheimer disease sialidosis, activity represents therapeutic approach to broadly regulate microglia-mediated neuroinflammation.

Language: Английский

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Acidic Nanoparticles Restore Lysosomal Acidification and Rescue Metabolic Dysfunction in Pancreatic β-Cells under Lipotoxic Conditions

ACS Nano, Journal Year: 2024, Volume and Issue: 18(24), P. 15452 - 15467

Published: June 3, 2024

Type 2 diabetes (T2D), a prevalent metabolic disorder lacking effective treatments, is associated with lysosomal acidification dysfunction, as well autophagic and mitochondrial impairments. Here, we report series of biodegradable poly(butylene tetrafluorosuccinate-co-succinate) polyesters, comprising 1,4-butanediol linker varying ratios tetrafluorosuccinic acid (TFSA) succinic components, to engineer lysosome-acidifying nanoparticles (NPs). The synthesized NPs are spherical diameters ≈100 nm have low polydispersity good stability. Notably, TFSA NPs, which composed entirely TFSA, exhibit the strongest degradation capability superior acidifying properties. We further reveal significant downregulation vacuolar (H+)-ATPase subunits, responsible for maintaining acidification, in human T2D pancreatic islets, INS-1 β-cells under chronic lipotoxic conditions, tissues high-fat-diet (HFD) mice. Treatment restores function, activity, thereby improving function cells HFD mice lipid overload. Importantly, administration reduces insulin resistance improves glucose clearance. These findings highlight therapeutic potential T2D.

Language: Английский

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Comprehensive Overview of Alzheimer’s Disease: Etiological Insights and Degradation Strategies

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 6901 - 6901

Published: June 24, 2024

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and affects millions of individuals globally. AD associated with cognitive decline memory loss that worsens aging. A statistical report using U.S. data on estimates approximately 6.9 million suffer from AD, a number projected to surge 13.8 by 2060. Thus, there critical imperative pinpoint address its hallmark tau protein aggregation early prevent manage debilitating effects. Amyloid-β proteins are primarily formation plaques neurofibril tangles in brain. Current research efforts focus degrading amyloid-β or inhibiting their synthesis, particularly targeting APP processing hyperphosphorylation, aiming develop effective clinical interventions. However, navigating this intricate landscape requires ongoing studies trials treatments truly make difference. Genome-wide association (GWASs) across various cohorts identified 40 loci over 300 genes AD. Despite wealth genetic data, much remains be understood about functions these role process, prompting continued investigation. By delving deeper into associations, novel targets such as kinases, proteases, cytokines, degradation pathways, offer new directions for drug discovery therapeutic intervention This review delves biological pathways disrupted identifies how variations within could serve potential treatment strategies. Through comprehensive understanding molecular underpinnings researchers aim pave way more therapies can alleviate burden devastating disease.

Language: Английский

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Role of metabolic dysfunction and inflammation along the liver–brain axis in animal models with obesity-induced neurodegeneration

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(4), P. 1069 - 1076

Published: May 17, 2024

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease Parkinson’s disease. Obesity-related conditions like type 2 diabetes non-alcoholic fatty liver exacerbate this relationship. Peripheral lipid accumulation, particularly in liver, initiates a cascade inflammatory processes that extend brain, influencing critical regulatory regions. Ceramide palmitate, key components, along with transporters lipocalin-2 apolipoprotein E, contribute neuroinflammation by disrupting blood–brain barrier integrity promoting gliosis. insulin resistance further exacerbates brain neuroinflammation. Preclinical interventions targeting peripheral metabolism signaling pathways have shown promise reducing animal models. However, translating these findings clinical practice requires investigation into human subjects. In conclusion, dysfunction, inflammation, are integral neurodegeneration. Understanding complex mechanisms holds potential for identifying novel therapeutic targets improving outcomes diseases.

Language: Английский

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Lysosomal acidification impairment in astrocyte-mediated neuroinflammation

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 10, 2025

Abstract Astrocytes are a major cell type in the central nervous system (CNS) that play key role regulating homeostatic functions, responding to injuries, and maintaining blood-brain barrier. also regulate neuronal functions survival by modulating myelination degradation of pathological toxic protein aggregates. have recently been proposed possess both autophagic activity active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete cellular cargos. Defective lysosomal acidification astrocytes impairs their resulting accumulation debris, excessive myelin lipids, aggregates, ultimately contributes propagation neuroinflammation neurodegenerative pathology. Restoration impaired represent new neuroprotective strategy therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, lipid mediated toxicity, contribute impairment associated dysfunction astrocytes. We discuss astrocyte-mediated primarily context diseases along with other brain injuries. then highlight re-acidification as restore well degradative capacity conclude providing future perspectives phagocytes crosstalk CNS cells impart or effects.

Language: Английский

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Artesunate demonstrates neuroprotective effect through activation of lysosomal function and inhibition of cGAS-STING pathway

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110426 - 110426

Published: March 1, 2025

Language: Английский

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