GSK-3 and Tau: A Key Duet in Alzheimer’s Disease

Cells, Journal Year: 2021, Volume and Issue: 10(4), P. 721 - 721

Published: March 24, 2021

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase with plethora of substrates. As modulator several cellular processes, GSK-3 has central position in cell metabolism and signaling, important roles both physiological pathological conditions. been associated number human disorders, such as neurodegenerative diseases including Alzheimer's disease (AD). contributes to the hyperphosphorylation tau protein, main component neurofibrillary tangles (NFTs), one hallmarks AD. further involved regulation different neuronal processes that are dysregulated during AD pathogenesis, generation amyloid-β (Aβ) peptide or Aβ-induced death, axonal transport, cholinergic function, adult neurogenesis synaptic function. In this review, we will summarize recent data about involvement these contributing pathology, mostly focusing on crucial interplay between protein. We discuss current development potential therapies targeting GSK-3-phosphorylated tau.

Language: Английский

---

Signal pathways in the treatment of Alzheimer’s disease with traditional Chinese medicine

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 152, P. 113208 - 113208

Published: May 31, 2022

This study aimed to reveal the classical signal pathways and important potential targets of traditional Chinese medicine (TCM) for treating Alzheimer's disease (AD), provide support further investigation on TCM its active ingredients.Literature survey was conducted using PubMed, Web Science, Google Scholar, CNKI, other databases, with "Alzheimer's disease," "traditional medicine," "medicinal herb," "Chinese "natural plant" as primary keywords.TCM could modulate related AD pathological progression, including NF-κB, Nrf2, JAK/STAT, ubiquitin-proteasome pathway, autophagy-lysosome pathway-related AMPK/mTOR, GSK-3/mTOR, PI3K/Akt/mTOR, well SIRT1 PPARα pathway. It regulate crosstalk between through a multitarget, thus maintaining chronic inflammatory interaction balance, inhibiting oxidative stress damage, regulating system function, modulating autophagy, eventually improving cognitive impairment in patients AD.TCM be multilevel, multitargeted, multifaceted prevent treat AD. In-depth research prevention treatment new ideas exploring pathogenesis developing anti-AD drugs.

Language: Английский

---

Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: Jan. 21, 2022

The protein kinase, GSK-3, participates in diverse biological processes and is now recognized a promising drug discovery target treating multiple pathological conditions. Over the last decade, range of newly developed GSK-3 inhibitors chemotypes inhibition modes has been developed. Even more conspicuous dramatic increase indications that were tested from mood behavior disorders, autism cognitive disabilities, to neurodegeneration, brain injury pain. Indeed, clinical pre-clinical studies largely expanded uncovering new mechanisms novel insights into contribution neurodegeneration central nerve system (CNS)-related disorders. In this review we summarize developments field describe use variety CNS This remarkable volume information being generated undoubtedly reflects great interest, as well intense hope, developing potent safe practice.

Language: Английский

---

Disentangling tau: One protein, many therapeutic approaches

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(2), P. e00321 - e00321

Published: Jan. 25, 2024

The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy collectively impact millions patients their families worldwide. Despite years drug development using a variety mechanisms action, no therapeutic directed against has been approved for clinical use. This raises important questions about our current model pathology invites thoughtful consideration approach to nonclinical models trial design. In this article, we review what is known biology genetics tau, placing it in context failed trials. We highlight potential reasons lack success date offer suggestions new pathways development. Overall, viewpoint future optimistic group diseases.

Language: Английский

---

The roles of intrinsically disordered proteins in neurodegeneration

Biochimica et Biophysica Acta (BBA) - General Subjects, Journal Year: 2025, Volume and Issue: unknown, P. 130772 - 130772

Published: Feb. 1, 2025

Language: Английский

---

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(16), P. 9098 - 9098

Published: Aug. 23, 2021

Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial neurodegeneration context, deregulation of all three PKs has linked CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s (PD), frontotemporal lobar degeneration (FTLD), several neuromuscular disorders. The multifactorial nature these diseases, along failure many advanced clinical trials, lengthy approval process novel drug strongly limited discovery. However, near-decade from 2010 2020, computer-assisted design strategies combined synthetic efforts develop potent selective inhibitors disease-modifying agents. In this review, we described both structural functional aspects involvement crosstalk pathological signaling pathways. Moreover, outlined attractive medicinal chemistry approaches multi-target applied overcome some limitations known discover improved modulators suitable blood–brain barrier (BBB) permeability drug-like properties.

Language: Английский

---

The link between metabolic syndrome and Alzheimer disease: A mutual relationship and long rigorous investigation

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 91, P. 102084 - 102084

Published: Oct. 5, 2023

Language: Английский

---

GSK3: A potential target and pending issues for treatment of Alzheimer's disease

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(7)

Published: July 1, 2024

Abstract Glycogen synthase kinase‐3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains Alzheimer's disease (AD) patients models. AD neurodegenerative disorder with diverse pathogenesis notable cognitive impairments, characterized by Aβ aggregation excessive tau phosphorylation. This article provides an overview GSK3's structure regulation, extensively analyzing its relationship factors. overactivation disrupts neural growth, development, function. It directly promotes phosphorylation, amyloid precursor (APP) cleavage, leading to formation, or indirectly triggers neuroinflammation oxidative damage. We also summarize preclinical research highlighting inhibition activity as primary therapeutic approach for AD. Finally, pending issues like lack highly specific affinity‐driven inhibitors, are raised expected be addressed future research. In conclusion, represents target treatment, filled hope, challenges, opportunities, obstacles.

Language: Английский

---

The role of glycogen synthase kinase 3 beta in neurodegenerative diseases

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: Sept. 15, 2023

Neurodegenerative diseases (NDDs) pose an increasingly prevalent threat to the well-being and survival of elderly individuals worldwide. NDDs include Alzheimer’s disease (AD), Parkinson’s (PD), Huntington’s (HD), amyotrophic lateral sclerosis (ALS), so on. They are characterized by progressive loss or dysfunction neurons in central peripheral nervous system share several cellular molecular mechanisms, including protein aggregation, mitochondrial dysfunction, gene mutations, chronic neuroinflammation. Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase that believed play pivotal role pathogenesis NDDs. Here we summarize structure physiological functions GSK3β explore its involvement We also discussed potential as therapeutic target.

Language: Английский

---

Role of brain renin–angiotensin system in depression: A new perspective

CNS Neuroscience & Therapeutics, Journal Year: 2023, Volume and Issue: 30(4)

Published: Nov. 12, 2023

Abstract Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression related to the deficiency serotonin (5HT), which derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in pathogenesis depression. Notably, renin–angiotensin system (RAS) depression, different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) angiotensin receptor blockers (ARBs) may be effective However, underlying mechanism for role dysregulated brain RAS‐induced remains speculative. Therefore, this review aimed revise conceivable ACEIs ARBs how these agents ameliorate Dysregulation RAS triggers development progression through reduction 5HT expression brain‐derived neurotrophic factor (BDNF) induction mitochondrial neuroinflammation. inhibition central classical ARBS activation non‐classical prevent regulating 5HT, BDNF,

Language: Английский

---