Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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Chronic effects of inflammation on tauopathies

The Lancet Neurology, Journal Year: 2023, Volume and Issue: 22(5), P. 430 - 442

Published: April 13, 2023

Language: Английский

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The contribution of an imbalanced redox signalling to neurological and neurodegenerative conditions

Free Radical Biology and Medicine, Journal Year: 2022, Volume and Issue: 194, P. 71 - 83

Published: Nov. 24, 2022

Language: Английский

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Functions of Astrocytes under Normal Conditions and after a Brain Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(9), P. 8434 - 8434

Published: May 8, 2023

In the central nervous system (CNS) there are a greater number of glial cells than neurons (between five and ten times more). Furthermore, they have functions (more eight functions). Glia comprises different types cells, those neural origin (astrocytes, radial glia, oligodendroglia) differentiated blood monocytes (microglia). During ontogeny, develop earlier (at fetal day 15 in rat) astrocytes later 21 rat), which could indicate their important crucial role CNS. Analysis phylogeny reveals that reptiles lower compared to humans this is reversed, as neurons. These data perhaps imply special involved many vital functions, including memory, learning processes. addition, mechanisms protect CNS through production antioxidant anti-inflammatory proteins clean extracellular environment help communicate correctly with each other. The inflammatory mediators prevent changes brain homeostasis. On contrary, excessive, or continued appears characteristic element diseases, such Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple (MS), neurodevelopmental bipolar disorder, schizophrenia, autism. drugs techniques been developed reverse oxidative stress and/or excess inflammation occurs but much remains be investigated. This review attempts highlight functional relevance normal neuropathological conditions by showing molecular cellular

Language: Английский

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RIPK1 Regulates Microglial Activation in Lipopolysaccharide-Induced Neuroinflammation and MPTP-Induced Parkinson’s Disease Mouse Models

Cells, Journal Year: 2023, Volume and Issue: 12(3), P. 417 - 417

Published: Jan. 26, 2023

Increasing evidence suggests a pivotal role of receptor-interacting protein kinase 1 (RIPK1), an initiator necroptosis, in neuroinflammation. However, the precise RIPK1 microglial activation remains unclear. In present study, we explored lipopolysaccharide (LPS)-induced neuroinflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice by using RIPK1-specific inhibitors necrostatin-1 (Nec-1) stable (Nec-1s). Nec-1/Nec-1s or siRNA inhibited production proinflammatory molecules phosphorylation RIPK1-RIPK3-MLKL cell death LPS-induced inflammatory LPS/QVD/BV6-induced necroptotic conditions BV2 cells. Detailed mechanistic studies showed that exerted anti-inflammatory effects modulating AMPK, PI3K/Akt, MAPKs, NF-κB signaling pathways LPS-stimulated Subsequent vivo gene expression inhibiting brains LPS-injected mice. Furthermore, exert neuroprotective MPTP-induced We found p-RIPK1 is mainly expressed microglia, thus may contribute to subsequent dopaminergic neurons These data suggest key regulator

Language: Английский

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Ginsenoside Rg1 alleviates chronic inflammation-induced neuronal ferroptosis and cognitive impairments via regulation of AIM2 - Nrf2 signaling pathway

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 330, P. 118205 - 118205

Published: April 17, 2024

Language: Английский

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Mitophagy and cGAS–STING crosstalk in neuroinflammation

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(8), P. 3327 - 3361

Published: May 13, 2024

Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS–STING pathway, crucial innate immunity. This pathway responds DNA and associated with cellular stress. Our review explores molecular details regulatory mechanisms of mitophagy pathway. We critically evaluated literature demonstrating how dysfunctional leads neuroinflammatory conditions, primarily through accumulation mitochondria, activating activation prompts production proinflammatory cytokines, exacerbating neuroinflammation. emphasizes interaction between Effective might suppress offering protection against Conversely, impaired may activate potentially leading chronic Additionally, we explored this influences neurodegenerative disorders, suggesting a common mechanism in such diseases. In conclusion, there need additional targeted research unravel complexities mitophagy–cGAS–STING interactions their role neurodegeneration. highlights potential therapies targeting these pathways, which could lead new treatments conditions. synthesis enhances our understanding foundations neuroinflammation opens therapeutic avenues disease research.

Language: Английский

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Neuroinflammaging: A Tight Line Between Normal Aging and Age-Related Neurodegenerative Disorders

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Aging in the healthy brain is characterized by a low-grade, chronic, and sterile inflammatory process known as neuroinflammaging. This condition, mainly consisting an up-regulation of response at level, contributes to pathogenesis age-related neurodegenerative disorders. Development this proinflammatory state involves interaction between genetic environmental factors, able induce epigenetic modifications. Indeed, exposure compounds, drugs, infections, can contribute modifications DNA methylome, histone fold proteins, nucleosome positioning, leading modulation neuroinflammatory responses. Furthermore, some modifiers, which combine interact during life course, modeling epigenome dynamics sustain, or dampen phenotype. The aim review summarize current knowledge about neuroinflammaging with particular focus on mechanisms underlying onset progression cascades central nervous system; furthermore, we describe diagnostic biomarkers that may increase accuracy help tailor therapeutic strategies patients diseases.

Language: Английский

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Characterizing molecular and synaptic signatures in mouse models of late‐onset Alzheimer's disease independent of amyloid and tau pathology

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(6), P. 4126 - 4146

Published: May 12, 2024

Abstract INTRODUCTION MODEL‐AD (Model Organism Development and Evaluation for Late‐Onset Alzheimer's Disease) is creating distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory progression of late‐onset disease (LOAD) more accurately. METHODS We created LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, humanized amyloid‐beta (Aβ). Mice were subjected a control diet or high‐fat/high‐sugar (LOAD2+HFD). assessed disease‐relevant outcome measures in plasma brain including neuroinflammation, Aβ, neurodegeneration, neuroimaging, multi‐omics. RESULTS By 18 months, LOAD2+HFD mice exhibited sex‐specific neuron loss, elevated insoluble Aβ42, increased neurofilament light chain (NfL), altered gene/protein expression related lipid metabolism synaptic function. Imaging showed reductions volume neurovascular uncoupling. Deficits acquiring touchscreen‐based cognitive tasks observed. DISCUSSION The comprehensive characterization reveals that this important preclinical studies seeking understand LOAD prior independent amyloid plaques tau tangles. Highlights unlike (e.g., fed diet, CD), presented subtle but significant loss neurons cortex, levels Ab42 brain, (NfL). Transcriptomics proteomics changes gene/proteins relating variety processes In vivo imaging revealed an age‐dependent reduction region (MRI) uncoupling (PET/CT). also demonstrated deficits acquisition tasks.

Language: Английский

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Differential contribution of THIK-1 K+ channels and P2X7 receptors to ATP-mediated neuroinflammation by human microglia

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Feb. 26, 2024

Abstract Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release IL-1β. Extracellular ATP a strong activator inducing K + efflux as key signaling event, suggesting that -permeable ion channels could have high therapeutic potential. In these include ATP-gated THIK-1 P2X7 receptors, but their interactions potential role in human brain are unknown. Using novel specific inhibitor combination with patch-clamp electrophysiology slices neocortex, we found generated main tonic conductance microglia sets resting membrane stimulated concentration-dependent manner only via metabotropic potentiation THIK-1. We further demonstrated was mandatory for ATP-evoked IL-1β release, which strongly suppressed blocking Surprisingly, contributed marginally to total presence ATP, dominated P2X7. This suggests previously unknown, -independent mechanism activation. Nuclear sequencing revealed almost selective expression while had much broader expression. Thus, inhibition be an effective and, contrast P2X7, microglia-specific strategy contain neuroinflammation. Graphical

Language: Английский

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