Tyrosine phosphorylation and palmitoylation of TRPV2 ion channel tune microglial beta-amyloid peptide phagocytosis DOI Creative Commons
Shaobin Yang, Yaqin Du, Yanhong Li

et al.

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

Published: Sept. 3, 2024

Alzheimer's disease (AD) is the leading form of dementia, characterized by accumulation and aggregation amyloid in brain. Transient receptor potential vanilloid 2 (TRPV2) an ion channel involved diverse physiopathological processes, including microglial phagocytosis. Previous studies suggested that cannabidiol (CBD), activator TRPV2, improves amyloid-β (Aβ) phagocytosis TRPV2 modulation. However, molecular mechanism Aβ remains unknown. In this study, we aimed to investigate involvement underlying mechanisms. Utilizing human datasets, mouse primary neuron microglia cultures, AD model mice, evaluate expression both vivo vitro. was expressed cortex, hippocampus, microglia.Cannabidiol (CBD) could activate sensitize channel. Short-term CBD (1 week) injection intraperitoneally (i.p.) reduced neuroinflammation phagocytic receptors, but long-term (3 administration induced suppressed receptors APP/PS1 mice. Furthermore, hyper-sensitivity mediated tyrosine phosphorylation at sites Tyr(338), Tyr(466), Tyr(520) protein kinase JAK1, these mutation partially dependence on its localization. While palmitoylated Cys 277 site blocking palmitoylation improved Moreover, it demonstrated dynamically regulated ZDHHC21. Overall, our findings elucidated intricate interplay between phosphorylation/dephosphorylation cysteine palmitoylation/depalmitoylation, which had divergent effects These provide valuable insights into mechanisms linking sensitivity, offer therapeutic strategies for managing AD.

Language: Английский

Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders DOI
Ashley N. Brandebura, Adrien Paumier, Tarik Seref Onur

et al.

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 24(1), P. 23 - 39

Published: Oct. 31, 2022

Language: Английский

Citations

260
Astrocyte biomarker signatures of amyloid-β and tau pathologies in Alzheimer’s disease DOI Creative Commons
João Pedro Ferrari‐Souza, Pâmela C.L. Ferreira, Bruna Bellaver

et al.

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 27(11), P. 4781 - 4789

Published: Aug. 10, 2022

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied associations cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like 1 (YKL-40) levels with amyloid-β (Aβ) tau pathologies. We assessed 121 individuals across aging AD clinical spectrum positron emission tomography (PET) imaging for Aβ ([

Language: Английский

Citations

85
Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology DOI Creative Commons
Prateek Kumar, Annie M Goettemoeller, Claudia Espinosa‐García

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 1, 2024

Abstract Dysfunction in fast-spiking parvalbumin interneurons (PV-INs) may represent an early pathophysiological perturbation Alzheimer’s Disease (AD). Defining proteomic alterations PV-INs can provide key biological and translationally-relevant insights. We used cell-type-specific in-vivo biotinylation of proteins (CIBOP) coupled with mass spectrometry to obtain native-state PV-IN proteomes. signatures include high metabolic translational activity, over-representation AD-risk cognitive resilience-related proteins. In bulk proteomes, were associated decline humans, progressive neuropathology humans the 5xFAD mouse model Aβ pathology. CIBOP stages pathology revealed increased mitochondria metabolism, synaptic cytoskeletal disruption decreased mTOR signaling, not apparent whole-brain Furthermore, we demonstrated pre-synaptic defects PV-to-excitatory neurotransmission, validating our findings. Overall, this study present proteomes PV-INs, revealing molecular insights into their unique roles resiliency AD pathogenesis.

Language: Английский

Citations

22
Subcellular visualization: Organelle-specific targeted drug delivery and discovery DOI
Xintian Shao,

Caicai Meng,

Wenjing Song

et al.

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 199, P. 114977 - 114977

Published: June 28, 2023

Language: Английский

Citations

37
Metabolic perspective of astrocyte dysfunction in Alzheimer's disease and type 2 diabetes brains DOI Open Access
Zheng Shen, Zhengyang Li, Mengting Yu

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 158, P. 114206 - 114206

Published: Jan. 5, 2023

The term type III diabetes (T3DM) has been proposed for Alzheimer's disease (AD) due to the shared molecular and cellular features between 2 (T2DM) insulin resistance-associated memory deficits cognitive decline in elderly individuals. Astrocytes elicit neuroprotective or deleterious effects AD progression severity. Patients with T2DM are at a high risk of impairment, targeting astrocytes might be promising alleviating neurodegeneration diabetic brain. Recent studies focusing on cell-specific activities brain have revealed important role metabolism (e.g., glucose metabolism, lipid metabolism), neurovascular coupling, synapses, synaptic plasticity. In this review, we discuss how their dysfunction result multiple pathological clinical from metabolic perspective potential comorbid mechanism these two diseases astrocytes.

Language: Английский

Citations

31
Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies DOI Creative Commons
Marco Antônio De Bastiani, Bruna Bellaver, Wagner S. Brum

et al.

Brain Behavior and Immunity, Journal Year: 2023, Volume and Issue: 110, P. 175 - 184

Published: March 4, 2023

Language: Английский

Citations

30
The Amyloid-Beta Clearance: From Molecular Targets to Glial and Neural Cells DOI Creative Commons
Wenjun Cai, Tong Wu, Ning Chen

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(2), P. 313 - 313

Published: Feb. 7, 2023

The deposition of amyloid-beta (Aβ) plaques in the brain is one primary pathological characteristics Alzheimer’s disease (AD). It can take place 20–30 years before onset clinical symptoms. imbalance between production and clearance Aβ major causes AD. Enhancing at an early stage attractive preventive therapeutic strategy Direct inhibition aggregation using small molecules, peptides, monoclonal antibody drugs has not yielded satisfactory efficacy trials for decades. Novel approaches are required to understand combat deposition. Neurological dysfunction a complex process that integrates functions different types cells brain. role non-neurons AD been fully elucidated. An in-depth understanding interactions neurons contribute elucidation formation identification effective drug targets. patient-derived pluripotent stem (PSCs) contain complete background information have potential differentiate into various vitro, which may bring new insight treatment Here, we systematically review latest studies on clarify roles cell among microglia, astroglia response plaques, will be beneficial explore methods reconstructing models inducible PSCs (iPSCs) through differentiation techniques validating applications plaques. This provide most promising directions finding clues preventing delaying development

Language: Английский

Citations

28
Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer’s Disease DOI Open Access
Atefeh Afsar, Maria del Carmen Chacon Castro,

Adedamola Saidi Soladogun

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(8), P. 7258 - 7258

Published: April 14, 2023

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, neurodegeneration. Diverse alterations have been associated with progression, including genetic mutations, neuroinflammation, blood-brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, metal ion imbalance.Additionally, recent studies shown an association between altered heme metabolism AD. Unfortunately, decades of research drug development not produced any effective treatments for Therefore, understanding the cellular molecular mechanisms underlying pathology identifying potential therapeutic targets are crucial development. This review discusses most common promising discovery. Furthermore, it highlights role in summarizes mathematical models AD, stochastic model effect Aβ on We also summarize treatment strategies these can offer clinical trials.

Language: Английский

Citations

23
Astrocytes: The Stars in Neurodegeneration? DOI Creative Commons
Katarina Stoklund Dittlau, Kristine Freude

Biomolecules, Journal Year: 2024, Volume and Issue: 14(3), P. 289 - 289

Published: Feb. 28, 2024

Today, neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, as the average human lifespan increases, similarly grows number patients. For many decades, cognitive motoric decline has been explained by very apparent deterioration neurons in various regions brain spinal cord. However, more recent studies show that progression is greatly influenced vast population glial cells. Astrocytes are traditionally considered star-shaped cells on which rely heavily for their optimal homeostasis survival. Increasing amounts evidence depict how astrocytes lose supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many these changes similar across diseases, this review, we highlight commonalities. We discuss astrocyte dysfunction drives neuronal demise a wide range but rather than categorizing based disease, aim to provide an overview currently known mechanisms. As such, review delivers different perspective causes neurodegeneration hope encourage further cross-disease into shared mechanisms, might ultimately disclose potentially common therapeutic entry points panel diseases.

Language: Английский

Citations

15
Novel Therapeutic Agents for Management of Diabetes Mellitus: A Hope for Drug Designing against Diabetes Mellitus DOI Creative Commons
Ahmed M. E. Elkhalifa,

Mehak Nazar,

Sofi Imtiyaz Ali

et al.

Life, Journal Year: 2024, Volume and Issue: 14(1), P. 99 - 99

Published: Jan. 8, 2024

Diabetes mellitus (DM) is characterized by an absolute decline in insulin secretion and peripheral resistance the most prevalent metabolic endocrine disorder. However, pathogenesis of DM also includes adipocyte resistance, increased glucagon secretion, renal glomerular glucose absorption, neurotransmitter dysfunction. Although there a wide spectrum therapeutics available for glycemic control, owing to identification various pathogenic determinants DM, management remains challenging complex. Current therapeutic interventions against focus mostly on control without considering other pathological that eventually lead treatment failure progression DM. Furthermore, long-term use these conventionally anti-diabetic drugs leads side effects, henceforth development novel unending search strategy researchers. Various studies conducted parts world have proposed target multiple alternate hotspots involved The current review article discusses options hold particular promise support their safety discuss effects resulting from so candidate can be effectively fabricated into potential

Language: Английский

Citations

11