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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Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

Molecules, Journal Year: 2020, Volume and Issue: 25(3), P. 564 - 564

Published: Jan. 28, 2020

Worldwide, 50 million people suffer from dementia, a group of symptoms affecting cognitive and social functions, progressing severely enough to interfere with daily life. Alzheimer's disease (AD) accounts for most the dementia cases. Pathological clinical findings have led proposing several hypotheses AD pathogenesis, finding presence positive feedback loops additionally observing disturbance branch tryptophan metabolism, kynurenine (KYN) pathway. Either causative or resultant elevated levels neurotoxic KYN metabolites are observed, potentially upregulating multiple pathogenesis. Memantine is an N-methyl-D-aspartate glutamatergic receptor (NMDAR) antagonist, which belongs one only two classes medications approved use, but other NMDAR modulators been explored so far in vain. An endogenous pathway metabolite, kynurenic acid (KYNA), likewise inhibits excitotoxic NMDAR. Besides its anti-excitotoxicity, KYNA multitarget compound that triggers anti-inflammatory antioxidant activities. Modifying level potential strategy normalize disturbed thus alleviate juxtaposing pathogeneses. In this review, maintenance metabolism by modifying proposed discussed search novel lead against progression dementia.

Language: Английский

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Cholinesterase Inhibitors for Alzheimer's Disease: Multitargeting Strategy Based on Anti-Alzheimer's Drugs Repositioning

Current Pharmaceutical Design, Journal Year: 2019, Volume and Issue: 25(33), P. 3519 - 3535

Published: Oct. 8, 2019

In the brain, acetylcholine (ACh) is regarded as one of major neurotransmitters. During advancement Alzheimer's disease (AD) cholinergic deficits occur and this can lead to extensive cognitive dysfunction decline. Acetylcholinesterase (AChE) remains a highly feasible target for symptomatic improvement AD. viable in AD because deficit consistent early finding The treatment approach inhibiting peripheral AChE myasthenia gravis had effectively proven that inhibition was reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, galantamine were developed approved Since then, multiple cholinesterase inhibitors (ChEIs) have been continued be developed. These include newer ChEIs, naturally derived hybrids, synthetic analogues. paper, we summarize different types ChEIs which are under development their respective mechanisms actions.

Language: Английский

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Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease

Neurology, Journal Year: 2018, Volume and Issue: 91(3), P. 125 - 132

Published: June 13, 2018

Impaired synaptic plasticity and dendritic loss in excitatory glutamatergic synapses are early events Alzheimer disease (AD). These abnormalities triggered by accumulation of soluble fibrillary β-amyloid (Aβ) oligomers, which bind to several postsynaptic presynaptic partners. Many the effects Aβ oligomers involve NMDA receptors (NMDARs) type 1 metabotropic glutamate receptor 5 (mGluR5). mediate use-dependent hippocampus other brain regions. Synaptic includes long-term potentiation (LTP) depression (LTD) efficacy transmission. Studies both vitro animal models indicate that disrupt LTP promote LTD; these associated with decreased density spines. The mechanisms elicit changes similar those normally utilized CNS during development learning. In addition, interactions β extrasynaptic NMDARs mGluR5 tau-hyperphosphorylation, leading impaired mitochondrial transport thus disrupting calcium homeostasis energy-dependent processes. Via activation glial cells, triggers complement-mediated pruning vulnerable synapses. Loss spines precedes neuritic plaques neurofibrillary tangles is potentially reversible. multiple potential may trigger dysfunction provide targets for neuroprotective therapy. There reviews focused on topics.1–11 Only selected aspects its involvement AD reviewed here.

Language: Английский

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The Neurovascular Unit Dysfunction in Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(4), P. 2022 - 2022

Published: Feb. 18, 2021

Alzheimer’s disease (AD) is the most common neurodegenerative worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in brain parenchyma as neuritic plaques, around blood vessels cerebral angiopathy (CAA). According to vascular hypothesis AD, risk factors can result dysregulation neurovascular unit (NVU) hypoxia. Hypoxia may reduce Aβ clearance from increase its production, leading parenchymal accumulation Aβ. An amplifies neuronal dysfunction, NFT formation, accelerates neurodegeneration, resulting dementia. In recent decades, therapeutic approaches have attempted decrease levels abnormal or tau brain. However, several these either been associated an inappropriate immune response triggering inflammation, failed improve cognition. Here, we review pathogenesis potential targets dysfunction NVU AD.

Language: Английский

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NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2021, Volume and Issue: 83(3), P. 939 - 961

Published: Aug. 6, 2021

Alzheimer’s disease (AD) is the most prevalent neurodegenerative commonly diagnosed among elderly population. AD characterized by loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to extracellular accumulation senile plaques, composed insoluble aggregates amyloid-β (Aβ) peptides, intraneuronal formation neurofibrillary tangles shaped hyperphosphorylated filaments microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release proinflammatory cytokines reactive glial cells, contribute pathophysiology disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor wide range stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review recent findings regarding involvement pathogenesis We address mechanisms priming activation cells Aβ species potential role vesicles progression. Neuronal death NLRP3-mediated pyroptosis, driven interneuronal tau propagation, also discussed. present considerable claim inhibition, undoubtfully therapeutic strategy for

Language: Английский

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Excitotoxicity as a Target Against Neurodegenerative Processes

Current Pharmaceutical Design, Journal Year: 2020, Volume and Issue: 26(12), P. 1251 - 1262

Published: Jan. 14, 2020

: The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging population. Although molecular mechanisms leading neurodegeneration are not completely understood, excitotoxicity, defined as injury and death neurons due excessive or prolonged exposure excitatory amino acids, has been shown play a pivotal role. increased release and/or decreased uptake glutamate results dysregulation neuronal calcium homeostasis, oxidative stress, mitochondrial dysfunctions, disturbances protein turn-over neuroinflammation. Despite anti-excitotoxic drug memantine modest beneficial effects some patients with dementia, date, there no effective treatment capable halting curing such Alzheimer’s disease, Parkinson Huntington’s disease amyotrophic lateral sclerosis. This led growing body research focusing on understanding associated excitotoxic insult uncovering potential therapeutic strategies targeting these mechanisms. In present review, we examine related cell death. Moreover, provide comprehensive updated state art preclinical clinical investigations excitotoxic- order an against neurodegeneration.

Language: Английский

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Indian Medicinal Herbs and Formulations for Alzheimer’s Disease, from Traditional Knowledge to Scientific Assessment

Brain Sciences, Journal Year: 2020, Volume and Issue: 10(12), P. 964 - 964

Published: Dec. 10, 2020

Cognitive impairment, associated with ageing, stress, hypertension and various neurodegenerative disorders including Parkinson’s disease epilepsy, is a major health issue. The present review focuses on Alzheimer’s (AD), since it the most important cause of cognitive impairment. It characterized by progressive memory loss, language deficits, depression, agitation, mood disturbances psychosis. Although hallmarks AD are cholinergic dysfunction, β-amyloid plaques neurofibrillary tangle formation, also derangement other neurotransmitters, elevated levels advanced glycation end products, oxidative damage, neuroinflammation, genetic environmental factors. On one hand, this complex etiopathology makes response to commonly used drugs such as donepezil, rivastigmine, galantamine memantine less predictable often unsatisfactory. supports use herbal medicines due their nonspecific antioxidant anti-inflammatory activity specific cholinesterase inhibitory activity. popularity increasing perceived effectiveness, safety affordability. In article, experimental clinical evidence have been reviewed for Indian Centella asiatica, Bacopa monnieri, Curcuma longa, Clitoria ternatea, Withania somnifera, Celastrus paniculatus, Evolvulus alsinoides, Desmodium gangeticum, Eclipta alba, Moringa oleifera Convolvulus pluricaulis, which shown potential in Some available formulations impairment India reviewed.

Language: Английский

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Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(10), P. 3719 - 3719

Published: May 25, 2020

Mitochondria play a central role in plethora of processes related to the maintenance cellular homeostasis and genomic integrity. They contribute preserving optimal functioning cells protecting them from potential DNA damage which could result mutations disease. However, perturbations system due senescence or environmental factors induce alterations physiological balance lead impairment mitochondrial functions. After description crucial roles mitochondria for cell survival activity, core this review focuses on “mitochondrial switch” occurs at onset neuronal degeneration. We dissect pathways dysfunctions are shared among most frequent disabling neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy. Can (affecting their morphology activities) represent early event eliciting shift towards pathological neurobiological processes? common target against neurodegeneration? also here drugs that diseases.

Language: Английский

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New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer’s Disease and Its Potential for Therapeutic Intervention

Cells, Journal Year: 2022, Volume and Issue: 11(12), P. 1925 - 1925

Published: June 14, 2022

Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 by 2050. The exact pathogenic mechanisms AD remain elusive, resulting in fact that current therapeutics solely focus on symptomatic management instead preventative or curative strategies. two widely accepted include amyloid and tau hypotheses. However, it evident these hypotheses cannot fully explain neuronal degeneration shown AD. Substantial evidence growing for vital role neuroinflammation pathology. neuroinflammatory hypothesis provides a new, exciting lead uncovering underlying contributing This review aims highlight new insights into pathogenesis AD, mainly including involvement nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB), nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3)/caspase-1 axis, triggering receptor expressed myeloid 2 (TREM2) cGAS-STING as key influencers augmenting development. inflammasomes related pathways NF-κB, NLRP3, TREM2, biomarkers associated well overview novel treatments based potential drug targets reported literature under clinical trials, are explored.

Language: Английский

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