The neuroinflammatory role of microglia in Alzheimer's disease and their associated therapeutic targets

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(7)

Опубликована: Июль 1, 2024

Abstract Introduction Alzheimer's disease (AD), the main cause of dementia, is characterized by synaptic loss and neurodegeneration. Amyloid‐β (Aβ) accumulation, hyperphosphorylation tau protein, neurofibrillary tangles (NFTs) in brain are considered to be initiating factors AD. However, this hypothesis falls short explaining many aspects AD pathogenesis. Recently, there has been mounting evidence that neuroinflammation plays a key role pathophysiology causes neurodegeneration over‐activating microglia releasing inflammatory mediators. Methods PubMed, Web Science, EMBASE, MEDLINE were used for searching summarizing all recent publications related inflammation its association with disease. Results Our review shows how dysregulation influences pathology as well roles neuroinflammation, possible microglia‐associated therapeutic targets, top neuroinflammatory biomarkers, anti‐inflammatory drugs combat inflammation. Conclusion In conclusion, microglial reactions important pathogenesis need discussed more detail promising strategies.

Язык: Английский

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Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides

International Journal of Molecular Sciences, Год журнала: 2022, Номер 24(1), С. 587 - 587

Опубликована: Дек. 29, 2022

The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage ALS patients having known genetic risk factor. article looks integrate wider bodies data on the biological underpinnings ALS, highlighting integrative role alterations mitochondrial melatonergic pathways systemic factors regulating this pathway across number crucial hubs pathophysiology, namely glia, gut, muscle/neuromuscular junction. It is proposed that suppression underpins changes muscle brain-derived neurotrophic factor, its mimic, N-acetylserotonin, leading lack metabolic trophic support at neuromuscular attenuation astrocytes prevents activation toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, yin yang 1, from built-in limitation inflammatory induction arises their synchronized melatonin release. Such maintained astrocyte activation, coupled heightened microglia reactivity, an important driver susceptibility ALS. Two gut dysbiosis/permeability pineal mediate many beneficial effects via capacity upregulate central cells. may seen as core aspect cellular function, increasing reactive oxygen species (ROS), ROS-induced microRNAs, thereby altering patterning genes induced. increased occupational farmers, gardeners, sportsmen women intimately linked exposure, whilst being physically active, widely used glyphosate-based herbicides. This has numerous research treatment implications.

Язык: Английский

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BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Май 4, 2023

Abstract Background Abnormal accumulation of amyloid beta peptide (Aβ) in the brain induces a cascade pathological changes Alzheimer’s disease (AD), and inhibiting BACE1, which is required for Aβ generation, therefore being explored treatment AD by reducing accumulation. As Bace1 knockout mice exhibit increased number reactive astrocytes brains have that surround plaques, we investigated role BACE1 determined whether regulates astrocytic functions. Methods We conducted unbiased single cell RNA-seq (scRNA-seq) using purified from KO wild type control littermates. Similar scRNA-seq was also with conditional deletion adult stage ( 5xFAD;Bace1 fl/fl ;UBC-creER compared to controls). transcriptomes astrocyte clusters identified several differentially expressed genes, were further validated cultures. Mice astrocyte-specific 5xFAD background used compare deposition. Mechanistic studies cultured identify substrates gene expression signaling activity. Results Among altered Clusterin Clu ) Cxcl14 significantly upregulated measuring protein levels. Moreover, deficiency enhanced both uptake degradation, this effect attenuated siRNA knockdown . study suggests abolishes cleavage insulin receptors (IR), may enhance Acutely isolated ;Gfap-cre show similar increases CLU IR. Furthermore, resulted significant attenuation cortical plaque load through clearance. Conclusion Together, our , likely via receptor pathway, inhibition potential alternative strategy enhancing

Язык: Английский

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Application of biomarker-derived fluorescent probes for the detection of Alzheimer's disease

TrAC Trends in Analytical Chemistry, Год журнала: 2023, Номер 169, С. 117369 - 117369

Опубликована: Окт. 12, 2023

Язык: Английский

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Virtual screening, ADMET prediction, molecular docking, and dynamic simulation studies of natural products as BACE1 inhibitors for the management of Alzheimer’s disease

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Ноя. 2, 2024

Alzheimer's disease (AD) is a degenerative neurological disorder that chronically and irreversibly affects memory, cognitive function, learning ability, organizational skills. Numerous studies have demonstrated BACE1 as critical therapeutic target for AD, emphasizing the need specific inhibition of to develop effective therapeutics. However, current inhibitors certain limitations. Therefore, aim this study was identify potential novel candidates derived from natural products can be utilized treatment AD. To achieve this, 80,617 compounds ZINC database were subjected virtual screening subsequently filtered according rule five (RO5), leading identification 1,200 compounds. Subsequently, underwent molecular docking against receptor, utilizing high-throughput (HTVS), standard precision (SP), extra (XP) techniques high-affinity ligands. Of 50 ligands exhibited highest G-Scores in HTVS, further analysis conducted using SP scoring methods. This led seven with enhanced binding affinities, which then additional via XP scoring. Finally, stability most promising ligand relation assessed through dynamics (MD) simulations. The computational energy values enzymes ranged between − 6.096 7.626 kcal/mol. Among these, 2 (L2) best at -7.626 kcal/mol BACE1. MD simulations confirmed BACE1-L2 complex, formation robust interaction L2 enzymes. Additionally, pharmacokinetic drug-likeness evaluations indicated non-carcinogenic able permeate blood-brain barrier (BBB). findings will contribute narrowing down selection subsequent vitro vivo testing.

Язык: Английский

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Polydopamine/Ruthenium Nanoparticle Systems as Photothermal Therapy Reagents and Reactive Oxygen Species Scavengers for Alzheimer’s Disease Treatment

ACS Applied Nano Materials, Год журнала: 2023, Номер 6(7), С. 5384 - 5393

Опубликована: Апрель 5, 2023

The important causes of microglial dysfunction include continuous accumulation amyloid beta (Aβ) fibrils, elevated reactive oxygen species (ROS), and hypoxia. They may be the key pathogenic mechanism Alzheimer's disease (AD). Photothermal therapy (PTT) is considered an innovative noninvasive alternative due to its huge potential, which modulated decomposition mature Aβ fibrils. Here, we report a polydopamine-ruthenium nanosystem (PDA-Ru) that simultaneously used as near-infrared PTT reagent, ROS scavenger, hydrogen peroxide catalyst. photothermal conversion performance catalase activity PDA were improved by anchoring Ru nanoparticles small size. In vivo studies demonstrate PDA-Ru + NIR decreases deposition successfully, thereby restoring neuroregulatory function microglia. Ultimately, it ameliorates neuroinflammation memory deficits in AD mice. conclusion, work illustrates versatile nanomaterial can rescue neuronal damage modulate It could serve potential strategy for treatment other neurodegenerative diseases.

Язык: Английский

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Microglial Dyshomeostasis: A Common Substrate in Neurodevelopmental and Neurodegenerative Diseases

Neuroglia, Год журнала: 2024, Номер 5(2), С. 119 - 128

Опубликована: Май 12, 2024

Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity (ADHD) are clinically distinct, yet share synaptic dysfunction a common brain pathophysiology. Neurodegenerative diseases Huntington’s disease (HD) entail neuroinflammatory cascade of molecular cellular events which can contribute to the death neurons. Emerging roles for supportive glial cells microglia astrocytes in ongoing regulation neural synapses excitability raise possibility that some pathology and/or inflammatory could be direct consequence malfunctioning cells. Focusing on microglia, we cross-examined 12 recently published studies microglial was induced/identified cell-autonomous manner its functional development, volume, connectivity, response were evaluated; many cases, onset symptoms relevant all three neurodevelopmental assessed behaviorally. Challenging classic notion activation an neuropathology, our compilation clarifies dyshomeostasis itself consequently disrupt homeostasis, leading neuropathology symptom onset. This further warranted defining signatures context-specific human diseases.

Язык: Английский

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Neuroprotective Effects of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) against Amyloid-β-Induced Alzheimer’s Disease Mouse Model

Nutrients, Год журнала: 2023, Номер 15(23), С. 4986 - 4986

Опубликована: Дек. 1, 2023

Alzheimer’s disease (AD), is a progressive neurodegenerative disorder that involves the deposition of β-amyloid plaques and clinical symptoms confusion, memory loss, cognitive dysfunction. Despite enormous progress in field, no curative treatment available. Therefore, current study was designed to determine neuroprotective effects N-methyl-(2S, 4R)-Trans-4-hydroxy-L-proline (NMP) obtained from Sideroxylon obtusifolium, Brazilian folk medicine with anti-inflammatory anti-oxidative properties. Here, for first time, we explored role NMP Aβ1–42-injected mouse model AD. After acclimatization, single intracerebroventricular injection Aβ1–42 (5 µL/5 min/mouse) C57BL/6N mice induced significant amyloidogenesis, reactive gliosis, oxidative stress, neuroinflammation, synaptic deficits. However, an intraperitoneal at dose (50 mg/kg/day) three consecutive weeks remarkably decreased beta secretase1 (BACE-1) Aβ, activated astrocyte microglia expression level as well downstream inflammatory mediators such pNF-ĸB, TNF-α, IL-1β. NPM also strongly attenuated evaluated by NRF2/HO-1, failure, improving both presynaptic (SNAP-25 SYN) postsynaptic (PSD-95 SNAP-23) regions synapses cortexes hippocampi mice, contributing improvement AD behavioral deficits displayed Morris water maze Y-maze. Overall, our data suggest provides potent multifactorial effects, including inhibition amyloid plaques,

Язык: Английский

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Comparison between sub-chronic and chronic sleep deprivation-induced behavioral and neuroimmunological abnormalities in mice: Focusing on glial cell phenotype polarization

Behavioural Brain Research, Год журнала: 2024, Номер 470, С. 115067 - 115067

Опубликована: Май 23, 2024

Язык: Английский

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Neuroinflammation in Age-Related Neurodegenerative Diseases: Role of Mitochondrial Oxidative Stress

Antioxidants, Год журнала: 2024, Номер 13(12), С. 1440 - 1440

Опубликована: Ноя. 22, 2024

A shared hallmark of age-related neurodegenerative diseases is the chronic activation innate immune cells, which actively contributes to process. In Alzheimer’s disease, this inflammatory milieu exacerbates both amyloid and tau pathology. similar abnormal response has been reported in Parkinson’s with elevated levels cytokines other intermediates derived from activated glial promote progressive loss nigral dopaminergic neurons. Understanding causes that support aberrant become a topic growing interest research neurodegeneration, high translational potential. It postulated phenotypic shift cells towards proinflammatory state combined presence immunogenic cell death fuels vicious cycle mitochondrial dysfunction plays central role. Mitochondria mitochondria-generated reactive oxygen species are downstream effectors different signaling pathways, including inflammasomes. Dysfunctional mitochondria also recognized as important producers damage-associated molecular patterns, can amplify response. Here, we review major findings highlighting role checkpoint neuroinflammation deaths diseases. The knowledge these processes may help find new druggable targets modulate

Язык: Английский

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