Reactive astrocyte nomenclature, definitions, and future directions

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(3), P. 312 - 325

Published: Feb. 15, 2021

Language: Английский

---

The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications

The Lancet Neurology, Journal Year: 2019, Volume and Issue: 18(4), P. 406 - 414

Published: Feb. 19, 2019

Language: Английский

---

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: March 31, 2020

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout AD its continuum. Large-scale genome-wide association studies point out several genetic variants - TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, HLA-DRB5-HLA-DRB1 potentially linked to neuroinflammation. Most these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins cell turn-over, synaptic activity, lipid metabolism, vesicle trafficking. Proteomic indicate that a plethora interconnected aberrant molecular pathways, set off perpetuated by TNF-α, TGF-β, IL-1β, receptor protein Microglia astrocytes key cellular drivers regulators Under physiological conditions, they important for neurotransmission homeostasis. In AD, there is turning pathophysiological evolution where glial cells sustain an overexpressed inflammatory response synergizes with amyloid-β tau accumulation, drives synaptotoxicity neurodegeneration self-reinforcing manner. Despite strong therapeutic rationale, previous trials investigating compounds anti-inflammatory properties, including non-steroidal drugs (NSAIDs) did not achieve primary efficacy endpoints. It conceivable study design issues, lack diagnostic accuracy biomarkers target population identification proof-of-mechanism may partially explain negative outcomes. However, recent meta-analysis indicates potential biological effect NSAIDs. this regard, candidate fluid neuroinflammation under analytical/clinical validation, i.e. MCP-1, IL-6, TNF-α complexes, YKL-40. PET radio-ligands investigated accomplish in-vivo longitudinal regional exploration Biomarkers tracking different pathways (body matrixes) along brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between other mechanisms. Robust biomarker-drug co-development pipelines expected enrich large-scale testing new-generation active, directly or indirectly, on targets displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), AL003 (anti-CD33 antibody). As next step, taking advantage breakthrough multimodal techniques coupled systems biology approach path pursue developing individualized strategies targeting framework precision medicine.

Language: Английский

---

Astrocyte Biomarkers in Alzheimer’s Disease

Trends in Molecular Medicine, Journal Year: 2019, Volume and Issue: 25(2), P. 77 - 95

Published: Jan. 2, 2019

Language: Английский

---

Synaptic degeneration in Alzheimer disease

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 19(1), P. 19 - 38

Published: Dec. 13, 2022

Language: Английский

---

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

---

Deciphering the Astrocyte Reaction in Alzheimer’s Disease

Frontiers in Aging Neuroscience, Journal Year: 2018, Volume and Issue: 10

Published: April 25, 2018

Reactive astrocytes were identified as a component of senile amyloid plaques in the cortex Alzheimer's disease (AD) patients several decades ago. However, their role AD pathophysiology has remained elusive ever since, part owing to extrapolation literature from primary astrocyte cultures and acute brain injury models chronic neurodegenerative scenario. Recent accumulating evidence supports idea that reactive acquire neurotoxic properties, likely due both gain toxic function loss neurotrophic effects. diversity complexity this glial cell is only beginning be unveiled, anticipating reaction might heterogeneous well. Herein we review mouse human neuropathological studies attempt decipher main conundrums pose our understanding development progression. We discuss morphological features characterize brain, consequences for biology pathological hallmarks, molecular pathways have been implicated reaction.

Language: Английский

---

Questions and (some) answers on reactive astrocytes

Glia, Journal Year: 2019, Volume and Issue: 67(12), P. 2221 - 2247

Published: Aug. 19, 2019

Abstract Astrocytes are key cellular partners for neurons in the central nervous system. react to virtually all types of pathological alterations brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical is called astrogliosis or astrocyte reactivity. It long considered a nonspecific, secondary reaction conditions, offering no clues on disease‐causing mechanisms with little therapeutic value. However, many studies over last 30 years have underlined crucial active roles played astrocytes physiology, ranging from metabolic support, synapse maturation, pruning fine regulation synaptic transmission. prompted researchers explore how these new functions were changed disease, they reported them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that undergo massive changes gene expression when become reactive. observation further stressed reactive may be very different normal, nonreactive could influence disease outcomes. To make picture even more complex, both normal shown molecularly functionally heterogeneous. Very known about specific each subtype play contexts. In this review, we interrogated field identify discuss points consensus controversies astrocytes, starting their name. We then present emerging knowledge cells future challenges field.

Language: Английский

---

The Role of Astrocytes in the Central Nervous System Focused on BK Channel and Heme Oxygenase Metabolites: A Review

Antioxidants, Journal Year: 2019, Volume and Issue: 8(5), P. 121 - 121

Published: May 5, 2019

Astrocytes outnumber neurons in the human brain, and they play a key role numerous functions within central nervous system (CNS), including glutamate, ion (i.e., Ca2+, K+) water homeostasis, defense against oxidative/nitrosative stress, energy storage, mitochondria biogenesis, scar formation, tissue repair via angiogenesis neurogenesis, synapse modulation. After CNS injury, astrocytes communicate with surrounding neuronal vascular systems, leading to clearance of disease-specific protein aggregates, such as β-amyloid, α-synuclein. The astrocytic big conductance K+ (BK) channel plays these processes. Recently, potential therapeutic agents that target have been tested for their brain. In this review, we discuss BK antioxidant heme oxygenase metabolites following injury. A better understanding cellular molecular mechanisms astrocytes’ healthy diseased brains will greatly contribute development approaches Alzheimer’s disease, Parkinson’s stroke.

Language: Английский

---

Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders

Expert Opinion on Therapeutic Targets, Journal Year: 2019, Volume and Issue: 23(10), P. 865 - 882

Published: Oct. 3, 2019

Introduction: Adverse immune activation contributes to many central nervous system (CNS) disorders. All main CNS cell types express toll-like receptor 4 (TLR 4). This is critical for a myriad of functions such as cytokine secretion and phagocytic activity microglia; however, imbalances in TLR can contribute the progression neurodegenerative diseases.Areas covered: We considered available evidence implicating following pathologies: Alzheimer's disease, Parkinson's ischemic stroke, traumatic brain injury, multiple sclerosis, systems atrophy, Huntington's disease. reviewed studies reporting effects 4-specific antagonists agonists models peripheral diseases from perspective possible future use ligands disorders.Expert opinion: could suppress neuroinflammation by reducing overproduction inflammatory mediators; they may interfere with protein clearance mechanisms myelination. Agonists that specifically activate myeloid differentiation primary-response 88 (MyD88)-independent pathway signaling facilitate beneficial glial limited inducers proinflammatory mediators. Deciphering disease stage-specific involvement pathologies crucial clinical development antagonists.

Language: Английский

---