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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Extracellular vesicles from human‐induced pluripotent stem cell‐derived neural stem cells alleviate proinflammatory cascades within disease‐associated microglia in Alzheimer's disease

Journal of Extracellular Vesicles, Journal Year: 2024, Volume and Issue: 13(11)

Published: Nov. 1, 2024

Abstract As current treatments for Alzheimer's disease (AD) lack disease‐modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti‐inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)‐derived neural cells (NSCs) hold promise as a biologic AD. This study directly addressed this issue by examining the effects intranasal (IN) administrations hiPSC‐NSC‐EVs in 3‐month‐old 5xFAD mice. IN administered incorporated into microglia, including plaque‐associated encountered astrocyte soma processes brain. Single‐cell RNA sequencing revealed transcriptomic changes indicative diminished activation microglia astrocytes. Multiple genes linked to disease‐associated NOD‐, LRR‐, pyrin domain‐containing protein 3 (NLRP3)‐inflammasome interferon‐1 (IFN‐1) signalling displayed reduced expression microglia. Adding cultured challenged with amyloid‐beta oligomers resulted similar effects. Astrocytes also IFN‐1 interleukin‐6 signalling. Furthermore, modulatory on hippocampus persisted 2 months post‐EV treatment without impacting their phagocytosis function. Such were evidenced reductions microglial clusters inflammasome complexes, concentrations mediators, end products NLRP3 activation, and/or proteins involved p38/mitogen‐activated kinase signalling, unaltered The extent hypertrophy, plaques, p‐tau hippocampus. led cognitive mood Thus, early hiPSC‐NSC‐EV intervention can maintain reducing adverse neuroinflammatory cascades, plaque load, p‐tau. These results reflect first demonstration efficacy restrain cascades an model inducing activated reactive

Language: Английский

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MISEV2023 provides an updated and key reference for researchers studying the basic biology and applications of extracellular vesicles

Stem Cells Translational Medicine, Journal Year: 2024, Volume and Issue: 13(9), P. 848 - 850

Published: July 19, 2024

Abstract The recently published “Minimal information for studies of extracellular vesicles - 2023 (MISEV2023)” in the Journal Extracellular Vesicles has provided practical solutions to numerous challenges (EVs) researchers face. These guidelines are imperative novice and experienced promote unity within EV community. It is strongly recommended that laboratories working with EVs make MISEV2023 an essential handbook actively these during laboratory meetings, journal clubs, seminars, workshops, conferences. A collective effort from crucial steer progress science a positive direction.

Language: Английский

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Extracellular vesicles: translational research and applications in neurology

Nature Reviews Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Language: Английский

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Targeting of Extracellular Vesicle-Based Therapeutics to the Brain

Cells, Journal Year: 2025, Volume and Issue: 14(7), P. 548 - 548

Published: April 4, 2025

Extracellular vesicles (EVs) have been explored as promising vehicles for drug delivery. One of the most valuable features EVs is their ability to cross physiological barriers, particularly blood–brain barrier (BBB). This significantly enhances development EV-based delivery systems treatment CNS disorders. The present review focuses on factors and techniques that contribute successful therapeutics brain. Here, we discuss major methods brain targeting which includes utilization different administration routes, capitalizing biological origins EVs, modification through addition specific ligands surface EVs. Finally, current challenges in large-scale EV production loading while highlighting future perspectives regarding application

Language: Английский

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Extracellular vesicles from hiPSC-derived NSCs protect human neurons against Aβ-42 oligomers induced neurodegeneration, mitochondrial dysfunction and tau phosphorylation

Stem Cell Research & Therapy, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 18, 2025

Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta-42 (Aβ-42) in brain, causing various adverse effects. Thus, therapies that reduce Aβ-42 toxicity AD are great interest. One promising approach to use extracellular vesicles from human induced pluripotent stem cell-derived neural cells (hiPSC-NSC-EVs) because they carry multiple therapeutic miRNAs and proteins capable protecting neurons against Aβ-42-induced toxicity. Therefore, this vitro study investigated proficiency hiPSC-NSC-EVs protect oligomers (Aβ-42o) neurodegeneration. We isolated using chromatographic methods their size, ultrastructure, expression EV-specific markers getting incorporated into mature neurons. Next, differentiated two different hiPSC lines were exposed 1 µM Aβ-42o alone or with varying concentrations hiPSC-NSC-EVs. The protective effects Aβ-42o-induced neurodegeneration, oxidative stress, mitochondrial dysfunction, impaired autophagy, tau phosphorylation ascertained measures one-way ANOVA Newman-Keuls comparisons post hoc tests. A significant neurodegeneration was observed when alone. Neurodegeneration associated (1) elevated levels reactive oxygen species (ROS), superoxide, malondialdehyde (MDA) protein carbonyls (PCs), (2) increased proapoptotic Bax Bad genes proteins, encoding complex (3) diminished membrane potential mitochondria, (4) reduced antiapoptotic gene Bcl-2, autophagy-related (5) tau. However, addition an optimal dose (6 × 109 EVs) neuronal cultures significantly extent along ROS, MDA PCs, normalized expressions Bax, Bad, higher enhanced linked phosphorylation. An could decrease degeneration Aβ-42o. results support further research effectiveness AD, particularly preserving slowing progression.

Language: Английский

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Principal components analysis on genes related to inflammasome complex and microglial activation in the hypothalamus of obese mice treated with semaglutide (GLP-1 analog)

Brain Research, Journal Year: 2024, Volume and Issue: 1846, P. 149225 - 149225

Published: Sept. 6, 2024

Language: Английский

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Intranasally Administered EVs from hiPSC-derived NSCs Alter the Transcriptomic Profile of Activated Microglia and Conserve Brain Function in an Alzheimer's Model

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 20, 2024

Antiinflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural cells (NSCs) hold promise as a disease-modifying biologic for Alzheimer's disease (AD). This study directly addressed this issue by examining the effects of intranasal administrations hiPSC-NSC-EVs to 3-month-old 5xFAD mice. The EVs were internalized all microglia, which led reduced expression multiple genes associated with disease-associated inflammasome, and interferon-1 signaling. Furthermore, persisted two months post-treatment in hippocampus, evident microglial clusters, inflammasome complexes, proteins and/or linked activation inflammasomes, p38/mitogen-activated protein kinase, amyloid-beta (Aβ) plaques, Aβ-42, phosphorylated-tau concentrations also diminished, leading better cognitive mood function Thus, early intervention AD may help maintain brain restraining progression adverse neuroinflammatory signaling cascades.

Language: Английский

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Promise of mesenchymal stem cell-derived extracellular vesicles for alleviating subarachnoid hemorrhage-induced brain dysfunction by neuroprotective and antiinflammatory effects

Brain Behavior & Immunity - Health, Journal Year: 2024, Volume and Issue: 40, P. 100835 - 100835

Published: Aug. 3, 2024

Subarachnoid hemorrhage (SAH), accounting for ∼5% of all strokes, represents a catastrophic subtype cerebrovascular accident. SAH predominantly results from intracranial aneurysm ruptures and affects ∼30,000 individuals annually in the United States ∼6 per 100,000 people worldwide. Recent studies have implicated that administering mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) may be beneficial inducing neuroprotective antiinflammatory effects following SAH. EVs are nanosized particles bound by lipid bilayer. MSC-EVs comprise therapeutic cargo nucleic acids, lipids, proteins, having promise to ease SAH-induced long-term brain impairments. This review evaluated findings published on efficacy context A growing body evidence points out potential improving function animal models Specifically, demonstrated their ability reduce neuronal apoptosis neuroinflammation enhance neurological recovery through mechanisms. Such outcomes reported various suggest hold great as novel minimally invasive approach ameliorate damage improve patient outcomes. The also discusses limitations EV therapy required future research efforts toward harnessing full treating

Language: Английский

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FDA-approved cannabidiol [Epidiolex®] alleviates Gulf War Illness-linked cognitive and mood dysfunction, hyperalgesia, neuroinflammatory signaling, and declined neurogenesis

Military Medical Research, Journal Year: 2024, Volume and Issue: 11(1)

Published: Aug. 22, 2024

Abstract Background Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well persistent neuroinflammation oxidative stress. This study aimed to investigate the efficacy of Epidiolex ® , a Food Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function rat model chronic GWI. Methods Six months after exposure low doses GWI-related chemicals [pyridostigmine bromide, N,N -diethyl-meta-toluamide (DEET), permethrin (PER)] along with moderate stress, rats GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests conducted on 11 weeks treatment initiation evaluate performance tasks related associative recognition memory, object location pattern separation, sucrose preference. The effect hyperalgesia was also examined. tissues processed immunohistochemical molecular studies following behavioral tests. Results treated VEH exhibited impairments all anhedonia, whereas CBD-treated showed improvements no anhedonia. Additionally, alleviated rats. Analysis hippocampal from VEH-treated revealed astrocyte hypertrophy increased percentages activated microglia presenting NOD-, LRR- pyrin domain-containing protein 3 (NLRP3) complexes elevated levels proteins involved NLRP3 inflammasome activation Janus kinase/signal transducers activators transcription (JAK/STAT) signaling. Furthermore, there concentrations proinflammatory stress markers decreased neurogenesis. In contrast, hippocampus displayed reduced mediating inflammasomes JAK/STAT signaling, normalized cytokines markers, improved Notably, did not alter concentration endogenous cannabinoid anandamide hippocampus. Conclusions use an FDA-approved (Epidiolex ) has been shown effectively alleviate associated Importantly, observed this attributed ability significantly suppress signaling pathways that perpetuate neuroinflammation.

Language: Английский

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