Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: Aug. 17, 2022

Abstract Neuroinflammation is instigated by the misfiring of immune cells in central nervous system (CNS) involving microglia and astrocytes as key cell-types. a consequence CNS injury, infection, toxicity, or autoimmunity. It favorable well detrimental process for neurodevelopment associated processes. Transient activation inflammatory response release cytokines growth factors positively affects development post-injury tissue. However, chronic uncontrolled responses may lead to various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's (PD), amyotrophic lateral sclerosis, multiple sclerosis. These diseases have variable clinical pathological features, but are underlaid aggregation misfolded proteins with cytotoxic effect. Notably, abnormal glial could mediate neuroinflammation, leading condition. Microglia, type cell, resident form forefront defense system. Dysfunctional astrocyte, different kind cell homeostatic function, impairs protein aggregate (amyloid-beta plaque) clearance AD. Studies shown that undergo alterations their genetic profile, cellular molecular responses, thus promote dysfunctional cross-talk Hence, targeting astrocytes-driven pathways resolve particular layers neuroinflammation set reliable therapeutic intervention AD progression.

Language: Английский

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Alzheimer’s disease: Insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 211, P. 115522 - 115522

Published: March 28, 2023

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases that affect millions people worldwide, with both prevalence and incidence increasing age. It characterized by cognitive decline associated, specifically, degeneration cholinergic neurons. The problem this even more fundamental as available therapies remain fairly limited mainly focused on symptoms' relief. Although aetiology remains elusive, two main pathological hallmarks are described: i) presence neurofibrillary tangles formed unfolded protein aggregates (hyperphosphorylated Tau protein) ii) extracellular amyloid-beta peptide. Given complexity surrounding pathogenesis disease, several potential targets have been highlighted interrelated upon its progression, such oxidative stress accumulation metal ions. Thus, advances made development innovative multitarget therapeutical compounds to delay progression restore cell function. This review focuses ongoing research new insights emerging disease-modifying drugs for AD treatment. Furthermore, classical novel biomarkers early diagnosis their role in assisting improvement targeted will also be approached.

Language: Английский

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Role of Nrf2 in aging, Alzheimer’s and other neurodegenerative diseases

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 82, P. 101756 - 101756

Published: Oct. 13, 2022

Language: Английский

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Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

The increasing life expectancy has led to a higher incidence of age-related neurodegenerative conditions. Within this framework, neuroinflammation emerges as significant contributing factor. It involves the activation microglia and astrocytes, leading release pro-inflammatory cytokines chemokines infiltration peripheral leukocytes into central nervous system (CNS). These instances result in neuronal damage neurodegeneration through activated nucleotide-binding domain leucine-rich repeat containing (NLR) family pyrin protein 3 (NLRP3) nuclear factor kappa B (NF-kB) pathways decreased erythroid 2-related 2 (Nrf2) activity. Due limited effectiveness regarding inhibition neuroinflammatory targets using conventional drugs, there is challenging growth search for innovative therapies alleviating CNS diseases or even before their onset. Our results indicate that interventions focusing on Interleukin-Driven Immunomodulation, Chemokine (CXC) Receptor Signaling Expression, Cold Exposure, Fibrin-Targeted strategies significantly promise mitigate processes. approaches demonstrate potential anti-neuroinflammatory effects, addressing conditions such Multiple Sclerosis, Experimental autoimmune encephalomyelitis, Parkinson’s Disease, Alzheimer’s Disease. While findings are promising, immunomodulatory often face limitations due Immune-Related Adverse Events. Therefore, conduction randomized clinical trials matter mandatory, will pave way promising future development new medicines with specific therapeutic targets.

Language: Английский

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Neuroprotective and anti‐inflammatory effects of curcumin in Alzheimer's disease: Targeting neuroinflammation strategies

Phytotherapy Research, Journal Year: 2024, Volume and Issue: 38(6), P. 3169 - 3189

Published: April 14, 2024

Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid‐beta plaques and neurofibrillary tangles, leading to neuronal loss. Curcumin, polyphenolic compound derived from Curcuma longa , has shown potential neuroprotective effects due its anti‐inflammatory antioxidant properties. This review aims synthesize current preclinical data on anti‐neuroinflammatory mechanisms curcumin in context AD, addressing pharmacokinetics, bioavailability, as therapeutic adjunct. An exhaustive literature search was conducted, focusing recent studies within last 10 years related curcumin's impact neuroinflammation role AD. The methodology included sourcing articles specialized databases using specific medical subject headings terms ensure precision relevance. Curcumin demonstrates significant properties modulating neuroinflammatory pathways, scavenging reactive oxygen species, inhibiting production pro‐inflammatory cytokines. Despite potential, challenges remain regarding limited bioavailability scarcity comprehensive human clinical trials. emerges promising adjunct AD multimodal benefits. However, further research required overcome establish effective dosing regimens subjects. Developing novel delivery systems formulations may enhance treatment.

Language: Английский

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Molecular Mechanisms of Alzheimer’s Disease Induced by Amyloid-β and Tau Phosphorylation Along with RhoA Activity: Perspective of RhoA/Rho-Associated Protein Kinase Inhibitors for Neuronal Therapy

Cells, Journal Year: 2025, Volume and Issue: 14(2), P. 89 - 89

Published: Jan. 10, 2025

Amyloid-β peptide (Aβ) is a critical cause of Alzheimer's disease (AD). It generated from amyloid precursor protein (APP) through cleavages by β-secretase and γ-secretase. γ-Secretase, which includes presenilin, regulated several stimuli. Tau has also been identified as significant factor in AD. In particular, phosphorylation crucial for neuronal impairment, phosphorylated detaches microtubules, leading to the formation neurofibrillary tangles destabilization microtubule structure. This instability microtubules damages axons dendrites, resulting impairment. Notably, Aβ linked phosphorylation. Another AD neuroinflammation, primarily occurring microglia. Microglia possess receptors that bind with Aβ, triggering expression release an inflammatory factor, although their main physiological function phagocytose debris pathogens brain. NF-κB activation plays major role neuroinflammation. Additionally, production reactive oxygen species (ROS) microglia contributes this microglia, superoxide produced NADPH oxidase, specifically NOX2. Rho GTPases play essential regulating various cellular processes, including cytoskeletal rearrangement, morphology changes, migration, transcription. The typical involves actin filament formation. Neurons, complex processes synapse connections, rely on dynamics structural support. Other brain cells, such astrocytes, oligodendrocytes, depend specific structures maintain unique architectures. Thus, aberrant regulation activity can disrupt filaments, altered cell morphology, changes synapses, potentially contributing diseases

Language: Английский

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Reinforcing Nrf2 Signaling: Help in the Alzheimer’s Disease Context

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1130 - 1130

Published: Jan. 28, 2025

Oxidative stress plays a role in various pathophysiological diseases, including neurogenerative such as Alzheimer′s disease (AD), which is the most prevalent neuro-pathology aging population. has been reported to be one of earliest pathological alterations AD. Additionally, it was demonstrated that older adults, there loss free radical scavenging ability. The Nrf2 transcription factor key regulator antioxidant defense systems, but, with aging, both amount and transcriptional activity decrease. With available treatments for AD being poorly effective, reinforcing systems via pathway may way prevent treat To highlight predominant signaling defending against oxidative and, therefore, neurotoxicity, we present an overview natural compounds exert their own neuroprotective roles through activation pathway. This review opportunity promote holistic approach treatment need further refine development new potential Nrf2-targeting drugs.

Language: Английский

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Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer’s Disease through ApoE4/LRP1, Wnt3/β-Catenin/GSK3β, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model

Pharmaceuticals, Journal Year: 2022, Volume and Issue: 15(8), P. 1008 - 1008

Published: Aug. 17, 2022

Alzheimer's disease (AD) is a neurodegenerative disorder that associated with abnormal cognition. AD aided in its initiation and progression by hereditary environmental factors. Aluminum (Al) neurotoxic agent causes oxidative stress, which linked to progression. Additionally, Nrf2/HO-1, APOE4/LRP1, Wnt3/β-catenin, TLR4/NLRP3 are the main signaling pathways involved pathogenesis. Several phytochemicals promising options delaying evolution.This study aimed at studying neuroprotective effects of some as morin (MOR), thymol (TML), thymoquinone (TMQ) on physical mental activities (PhM) Al chloride (AlCl3)-induced rat model. Another objective was determine specificity using molecular docking.Eighty male Dawley rats were divided into eight groups. Each group received: saline (control group), AlCl3, (ALAD), PhM, either alone or combination MOR, TML, and/or TMQ for five weeks. Animals then subjected behavioral evaluation. Brain tissues used histopathological biochemical analyses extent neurodegeneration. The effect AlCl3-induced stress also investigated.AlCl3 caused decline spatial learning memory, well changes brains rats. Phytochemicals combined PhM restored antioxidant activities, increased HO-1 Nrf2 levels, blocked inflammasome activation, apoptosis, TLR4 expression, amyloide-β generation, tau hyperphophorylation. They brought ApoE4 LRP1 levels back normal regulated Wnt3/β-catenin/GSK3β pathway.The use strategy reducing modulating TLR4/NLRP3, Wnt3/β-catenin/GSK-3β pathways.

Language: Английский

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First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT₆ Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(2), P. 1580 - 1610

Published: Jan. 8, 2024

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as promising target for AD treatment; thus, here new series of 5-HT6R ligands with 1,3,5-triazine core selenoether linkers was explored. Among them, 2-naphthyl derivatives exhibited strong affinity selectivity over 5-HT1AR (13–15), 5-HT7R (14 15), 5-HT2AR (13). Compound 15 displayed high other central nervous system receptors low risk cardio-, hepato-, nephrotoxicity no mutagenicity, indicating its "drug-like" potential. also demonstrated neuroprotection against rotenone-induced neurotoxicity well antioxidant glutathione peroxidase (GPx)-like activity regulated pro-inflammatory genes NRF2 nuclear translocation. In rats, showed satisfying pharmacokinetics, penetrated blood–brain barrier, reversed MK-801-induced memory impairment, anxiolytic-like properties. 15's neuroprotective procognitive-like effects, stronger than those approved drug donepezil, may pave way use selenotriazines to inhibit both causes symptoms in therapy.

Language: Английский

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Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments

Open Medicine, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 1, 2025

Diabetes-related cognitive impairment is increasingly recognized as a significant complication, profoundly impacting patients' quality of life. This review aims to examine the pathophysiological mechanisms, clinical manifestations, risk factors, assessment and diagnosis, management strategies, future research directions in diabetes. A comprehensive literature search was conducted using PubMed, Medline, other medical databases identify, review, evaluate published articles on The focused studies examining pathophysiology, presentations, diagnostic approaches, strategies. current revealed that chronic hyperglycemia, insulin resistance, vascular factors are major contributing deficits Clinical manifestations include impairments attention, memory, executive function, visuospatial abilities, language. Risk encompass disease duration, glycemic control, presence complications, age, education level, comorbidities. Assessment tools screening instruments, neuropsychological testing, neuroimaging techniques. Management strategies involve control optimization, lifestyle modifications, training, pharmacological interventions. highlights prevalence impact diabetes, resulting from complex metabolic disturbances. Early detection multifaceted interventions crucial for preserving function improving patient outcomes. Future should focus neuroprotective biomarker identification, personalized approaches. Collaborative efforts between clinicians researchers essential effectively address this growing healthcare challenge enhance life individuals with diabetes-related impairment.

Language: Английский

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