scholarly journals PPARα Between Aspirin and Plaque Clearance

2019 ◽  
Vol 71 (2) ◽  
pp. 389-397 ◽  
Author(s):  
Sujyoti Chandra ◽  
Avik Roy ◽  
Dhruv R. Patel ◽  
Kalipada Pahan
Keyword(s):  
Plaque Clearance

scholarly journals IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Fátima Rivera-Escalera ◽  
Jonathan J. Pinney ◽  
Laura Owlett ◽  
Hoda Ahmed ◽  
Juilee Thakar ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Responses ◽  
Large Scale ◽  
Myeloid Cells ◽  
Amyloid Plaque ◽  
Plaque Burden ◽  
Cytokine Signaling ◽  
Expression Of Genes ◽  
Adenoviral Transduction ◽  
Plaque Clearance

Abstract Background Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. Methods To determine whether microglia are involved in IL-1β-induced plaque clearance, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of fibrillar Aβ (fAβ) was analyzed by flow cytometry and immunohistochemistry. To assess microglial proliferation, APP/PS1 mice transduced with IL-1β or control were injected intraperitoneally with BrdU and hippocampal tissue was analyzed by flow cytometry. RNAseq analysis was conducted on microglia FACS sorted from the hippocampus of control or IL-1β-treated APP/PS1 mice. These microglia were also sorted based on MX04 labeling (MX04+ and MX04− microglia). Results Resident microglia (CD45loCD11b+) constituted > 70% of the MX04+ cells in both Phe- and IL-1β-treated conditions, and < 15% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of fAβ internalized by individual microglia. Instead, IL-1β increased the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. In addition, transcriptomic analyses revealed that IL-1β treatment was associated with large-scale changes in the expression of genes related to immune responses, proliferation, and cytokine signaling. Conclusions These studies show that IL-1β overexpression early in amyloid pathogenesis induces a change in the microglial gene expression profile and an expansion of microglial cells that facilitates Aβ plaque clearance.

scholarly journals Interleukin-1β mediated amyloid plaque clearance is independent of CCR2 signaling in the APP/PS1 mouse model of Alzheimer's disease

2014 ◽  
Vol 69 ◽  
pp. 124-133 ◽  
Author(s):  
Fátima Rivera-Escalera ◽  
Sarah B. Matousek ◽  
Simantini Ghosh ◽  
John A. Olschowka ◽  
M. Kerry O’Banion
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Plaque ◽  
Interleukin 1Β ◽  
Model Of Alzheimer’S Disease ◽  
Plaque Clearance

scholarly journals Capturing Amyloid-β Oligomers by Stirring with Microscaled Iron Oxide Stir Bars into Magnetic Plaques to Reduce Cytotoxicity toward Neuronal Cells

Nanomaterials ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1284
Author(s):  
Yuan-Chung Tsai ◽  
Jing-Chian Luo ◽  
Te-I Liu ◽  
I-Lin Lu ◽  
Ming-Yin Shen ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Neuronal Cells ◽  
Amyloid Β ◽  
Specific Protein ◽  
M1 Polarization ◽  
Magnetic Stirring ◽  
Novel Strategy ◽  
Plaque Clearance ◽  
Ad Therapy ◽  
Phagocytic Uptake

Soluble amyloid-β oligomers (oAβ42)-induced neuronal death and inflammation response has been recognized as one of the major causes of Alzheimer’s disease (AD). In this work, a novel strategy adopting silica-coated iron oxide stir bar (MSB)-based AD therapy system via magnetic stirring-induced capture of oAβ42 into magnetic plaques (mpAβ42) and activation of microglia on cellular plaque clearance was developed. With oAβ42 being effectively converted into mpAβ42, the neurotoxicity toward neuronal cells was thus greatly reduced. In addition to the good preservation of neurite outgrowth through the diminished uptake of oAβ42, neurons treated with oAβ42 under magnetic stirring also exhibited comparable neuron-specific protein expression to those in the absence of oAβ42. The phagocytic uptake of mpAβ42 by microglia was enhanced significantly as compared to the counterpart of oAβ42, and the M1 polarization of microglia often occurring after the uptake of oAβ42 restricted to an appreciable extent. As a result, the inflammation induced by pro-inflammatory cytokines was greatly alleviated.

scholarly journals Therapeutic Actions of the Thiazolidinediones in Alzheimer’s Disease

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
María José Pérez ◽  
Rodrigo A. Quintanilla
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Cellular Damage ◽  
Brain Disorder ◽  
Cellular Targets ◽  
Progressive Neurodegeneration ◽  
Synaptic Failure ◽  
Plaque Clearance ◽  
Metabolic Brain Disorder

Alzheimer’s disease (AD) is a multifactorial metabolic brain disorder characterized by protein aggregates, synaptic failure, and cognitive impairment. In the AD brain is common to observe the accumulation of senile plaques formed by amyloid-beta (Aβ) peptide and the neurofibrillary tangles composed of modified tau protein, which both lead to cellular damage and progressive neurodegeneration. Currently, there is no effective therapy for AD; however several studies have shown that the treatments with the peroxisome proliferators activated receptor-gamma (PPARγ) agonists known as thiazolidinedione drugs (TZDs), like rosiglitazone and pioglitazone, attenuate neurodegeneration and improve cognition in mouse models and patients with mild-to-moderate AD. Furthermore, studies on animal models have shown that TZDs inhibit neuroinflammation, facilitate amyloid-βplaque clearance, enhance mitochondrial function, improve synaptic plasticity, and, more recently, attenuate tau hyperphosphorylation. How TZDs may improve or reduce these pathologic signs of AD and what the mechanisms and the implicated pathways in which these drugs work are are questions that remain to be answered. However, in this review, we will discuss several cellular targets, in which TZDs can be acting against the neurodegeneration.

scholarly journals IKK2/NF-κB Activation in Astrocytes Reduces Amyloid β Deposition: A Process Associated with Specific Microglia Polarization

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2669
Author(s):  
Shu Yang ◽  
Alexander Magnutzki ◽  
Najwa Ouali Alami ◽  
Michael Lattke ◽  
Tabea Melissa Hein ◽  
...  
Keyword(s):  
Marker Gene ◽  
Amyloid Β ◽  
Specific Marker ◽  
App Processing ◽  
Beneficial Effects ◽  
Gene Profiles ◽  
Microglia Polarization ◽  
App23 Mouse ◽  
Plaque Clearance ◽  
The Impact

Alzheimer’s disease (AD) is a common neurodegenerative disease that is accompanied by pronounced neuroinflammatory responses mainly characterized by marked microgliosis and astrogliosis. However, it remains open as to how different aspects of astrocytic and microglial activation affect disease progression. Previously, we found that microglia expansion in the spinal cord, initiated by IKK2/NF-κB activation in astrocytes, exhibits stage-dependent beneficial effects on the progression of amyotrophic lateral sclerosis. Here, we investigated the impact of NF-κB-initiated neuroinflammation on AD pathogenesis using the APP23 mouse model of AD in combination with conditional activation of IKK2/NF-κB signaling in astrocytes. We show that NF-κB activation in astrocytes triggers a distinct neuroinflammatory response characterized by striking astrogliosis as well as prominent microglial reactivity. Immunohistochemistry and Congo red staining revealed an overall reduction in the size and number of amyloid plaques in the cerebral cortex and hippocampus. Interestingly, isolated primary astrocytes and microglia cells exhibit specific marker gene profiles which, in the case of microglia, point to an enhanced plaque clearance capacity. In contrast, direct IKK2/NF-κB activation in microglia results in a pro-inflammatory polarization program. Our findings suggest that IKK2/NF-κB signaling in astrocytes may activate paracrine mechanisms acting on microglia function but also on APP processing in neurons.

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