Microglial activation states and their implications for Alzheimer's Disease

The Journal of Prevention of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: 12(1), P. 100013 - 100013

Published: Jan. 1, 2025

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by the accumulation of toxic amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) tau protein in brain. Microglia, key immune cells central nervous system, play an important role AD development progression, primarily through their responses to Aβ NFTs. Initially, microglia can clear Aβ, but AD, activation overwhelms protective mechanisms, leading sustained neuroinflammation that enhances plaque toxicity, setting off damaging cycle affects neurons, astrocytes, cerebral vasculature, other microglia. Current treatments have been largely ineffective, though emerging immunotherapies focusing on removal show promise, often overlook neuroinflammation. Activated display complex range phenotypes be broadly broken into pro- or anti-inflammatory states, although this dichotomy does not describe significant overlap between states. strongly induce inflammatory activity, triggering production reactive oxygen species, cytokines (e.g., TNF-α, IL-1β, IL-6), synapse engulfment, blood-brain barrier compromise, impaired clearance. These processes contribute neural tissue loss, manifesting as cognitive decline such executive function memory. Conversely, exerts neuroprotective effects suppressing pathways releasing neurotrophic factors aid neuron repair protection. Induction states may offer dual therapeutic approach address both AD. This suggests potential strategies modulate microglial phenotypes, aiming restore functions mitigate disease progression simultaneously targeting inflammation pathology.

Language: Английский

---

Enantiomer-Dependent Supramolecular Immunosuppressive Modulation for Tissue Reconstruction

ACS Nano, Journal Year: 2024, Volume and Issue: 18(6), P. 5051 - 5067

Published: Feb. 2, 2024

Modulating the properties of biomaterials in terms host immune response is critical for tissue repair and regeneration. However, it unclear how preference cellular microenvironment manipulates chiral responses under physiological or pathological conditions. Here, we reported that vivo vitro oligopeptide immunosuppressive modulation was achieved by manipulation macrophage polarization using tetrapeptide (Ac-FFFK-OH, marked as FFFK) supramolecular polymers. The results suggested FFFK nanofibers can serve a defense mechanism restoration homeostasis upregulating M2 via Src-STAT6 axis. More importantly, transiently acting STAT6, insufficient to induce sustained program, then passes baton EGR2, thereby continuously maintaining program. It worth noting L-chirality exhibits more potent effect inducing than does D-chirality, leading enhanced reconstruction. These findings elucidate crucial molecular signals mediate chirality-dependent immunosuppression damaged tissues while also providing an effective strategy regulating promoting injury based on self-assembling peptide design.

Language: Английский

---

Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer’s Disease

Cells, Journal Year: 2025, Volume and Issue: 14(3), P. 168 - 168

Published: Jan. 22, 2025

The recent approval of lecanemab highlights that the amyloid beta (Aβ) protein is an important pathological target in Alzheimer’s disease (AD) and further emphasizes significance neuroinflammatory pathways regulating Aβ accumulation. Indeed, accumulation triggers microglia activation, which are key mediators neuroinflammation. inflammatory responses this process can lead to neuronal damage functional decline. Microglia secrete proinflammatory cytokines accelerate death release anti-inflammatory growth factors contributing recovery protection. Thus, play a dual role neurodegeneration neuroprotection, complicating their function AD. Therefore, elucidating complex interactions between protein, microglia, neuroinflammation essential for developing new strategies treating This review investigates receptors involved activating aims enhance understanding how these processes impact AD, as well they be regulated. also analyzed studies reported existing literature ongoing clinical trials. Overall, will contribute regulatory mechanisms therapies slow progression

Language: Английский

---

Reactive Oxygen Species as a Common Pathological Link Between Alcohol Use Disorder and Alzheimer’s Disease with Therapeutic Implications

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3272 - 3272

Published: April 1, 2025

Chronic alcohol consumption leads to excessive production of reactive oxygen species (ROS), driving oxidative stress that contributes both use disorder (AUD) and Alzheimer's disease (AD). This review explores how ROS-mediated mitochondrial dysfunction neuroinflammation serve as shared pathological mechanisms linking these conditions. We highlight the role alcohol-induced damage in exacerbating neurodegeneration compare ROS-related pathways AUD AD. Finally, we discuss emerging therapeutic strategies, including antioxidants inflammasome inhibitors, target mitigate neurodegeneration. Understanding overlapping may provide new insights for preventing treating ROS-driven neurodegenerative disorders.

Language: Английский

---

Estradiol improves behavior in FAD transgenic mice that express APOE3 but not APOE4 after ovariectomy

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: April 29, 2024

Increasing evidence suggests that female individuals have a higher Alzheimer’s disease (AD) risk associated with post-menopausal loss of circulating estradiol (E 2 ). However, clinical data are conflicting on whether E lowers AD risk. One potential contributing factor is APOE . The greatest genetic for APOE4 , pronounced in post-menopause. Clinical impacts the response patients to replacement therapy. prevents, neutral, or promotes any positive effects unclear. Therefore, our goal was determine modulates impact behavior and pathology vivo To end, mice express human APOE3 (E3FAD) (E4FAD) overproduce Aβ42 were ovariectomized at either 4 months (early) 8 (late) treated vehicle months. In E3FAD mice, we found mitigated detrimental effect ovariectomy memory, no Aβ early paradigm only improved learning late paradigm. Although lowered E4FAD paradigm, there possibly due compared mice. learning/memory Collectively, these support idea that, presence pathology, supplementation

Language: Английский

---

Complement 3a induces the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms during the development and progression of Alzheimer’s disease

Neuroscience & Biobehavioral Reviews, Journal Year: 2024, Volume and Issue: 165, P. 105868 - 105868

Published: Aug. 30, 2024

Language: Английский

---

A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3

Alzheimer s Research & Therapy, Journal Year: 2023, Volume and Issue: 15(1)

Published: Dec. 15, 2023

Abstract Background Alzheimer’s disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aβ). APOE greatest genetic risk for AD with APOE4 increasing up to ~ 15-fold compared APOE3. Evidence suggests that levels lipidation apoE protein could regulate progression. In glia, lipidated via cholesterol efflux from intracellular pools, primarily ATP-binding cassette transporter A1 (ABCA1). Therefore, ABCA1 activity suggested be a therapeutic approach AD. CS-6253 (CS) novel mimetic was developed bind stabilize maintain its localization into plasma membrane therefore promoting efflux. The goal this study determine whether CS modulate lipidation, Aβ pathology, behavior in model expresses human overproduce Aβ. Methods vitro, APOE3 -glia or were treated CS. vivo, male female, E3FAD (5xFAD +/− / +/+ ) E4FAD mice intraperitoneal injection at early (from 4 8 months age) late ages 10 age). ApoE levels, and, measured western blot ELISA. assessed histochemistry Learning memory tested Morris Water Maze synaptic proteins Western blot. Results treatment increased primary glial cultures. young mice, soluble lipid-associated apoE, reduced oAβ insoluble as well deposition, improved levels. did not induce any benefits female groups when started later ages. Conclusions pathology only E3FAD, cohort least pathology. degree overproduction may impact ability targeting an effective therapeutic. This ABCA1-stabilizing works best conditions modest

Language: Английский

---

Neuroglia markers expression in the cingulate and retrosplenial cortex of mice after nonseptic dose of lipopolysaccharide

Sechenov Medical Journal, Journal Year: 2024, Volume and Issue: 15(3), P. 48 - 57

Published: Nov. 1, 2024

Aim . To study the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1) in cerebral cingulate retrosplenial cortex mice on Day 5 after intraperitoneal (i.p.) administration bacterial lipopolysaccharide (LPS) at dose with no nervous tissue inflammation provoked. Materials methods The work was performed 10 female C57BL/6 aged 90 ± 3 days. At same time for 4 days, animals group were intraperitoneally injected saline (0.9% NaCl), 2 E. coli LPS endotoxin a mg/kg/day. On fifth day, withdrawn from experiment by decapitation xylazine/tiletamine-zoletil premedication, which histological preparations made, stained antibodies to GFAP Iba1, number of: (1) GFAP-positive cells cytoplasmic areas, (2) positive reaction Iba1 counted using QuPath software. Groups compared Mann-Whitney U-test. Results Group significantly higher than 1, exactly 22.5 (8.0; 32.0) vs 9.0 (4.3; 17.0), respectively, p = 0.0038. Iba1-positive portions cytoplasm also 2, namely 207,5 (154,8; 295,8) 128 (89,3; 165,5), 0,014. Both groups showed neither signs inflammation, excessive blood supply nor hemorrhages, as well perivascular edema or leukocytic migration. Conclusion LPS, administered i.p. mg/kg/day allows assessment changes glia CNS damage there. In cortex, astrocytes increases, macrophages protein.

Language: Английский

---

Nitric oxide-mediated neuroinflammatory pathways as treatment targets in neurodegeneration

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 79 - 96

Published: Nov. 15, 2024

Language: Английский

---