scholarly journals Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity

2017 ◽  
Vol 214 (4) ◽  
pp. 1081-1092 ◽  
Author(s):  
Eva Czirr ◽  
Nicholas A. Castello ◽  
Kira I. Mosher ◽  
Joseph M. Castellano ◽  
Izumi V. Hinkson ◽  
...  
Keyword(s):  
In Vivo Microdialysis ◽  
Complement Receptor ◽  
Tissue Plasminogen ◽  
Amyloid Aβ ◽  
Small Molecule Modulator ◽  
Β Amyloid ◽  
Aβ Clearance ◽  
Complement Receptor 3 ◽  
The Complement System

Recent genetic evidence supports a link between microglia and the complement system in Alzheimer’s disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein–transgenic mice results in decreased, rather than increased, Aβ accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aβ by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aβ levels and Aβ half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aβ clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aβ metabolism and defining a potential new therapeutic target in AD.

Role of complement and Fcγ receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5170-5180 ◽  
Author(s):  
Federica Moalli ◽  
Andrea Doni ◽  
Livija Deban ◽  
Teresa Zelante ◽  
Silvia Zagarella ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Alternative Pathway ◽  
Complement Receptor ◽  
Protective Activity ◽  
Opsonic Activity ◽  
Reactive Protein ◽  
Complement Receptor 3 ◽  
Dependent Pathway

AbstractPentraxin 3 (PTX3) is a soluble pattern recognition molecule playing a nonredundant role in resistance against Aspergillus fumigatus. The present study was designed to investigate the molecular pathways involved in the opsonic activity of PTX3. The PTX3 N-terminal domain was responsible for conidia recognition, but the full-length molecule was necessary for opsonic activity. The PTX3-dependent pathway of enhanced neutrophil phagocytic activity involved complement activation via the alternative pathway; Fcγ receptor (FcγR) IIA/CD32 recognition of PTX3-sensitized conidia and complement receptor 3 (CR3) activation; and CR3 and CD32 localization to the phagocytic cup. Gene targeted mice (ptx3, FcR common γ chain, C3, C1q) validated the in vivo relevance of the pathway. In particular, the protective activity of exogenous PTX3 against A fumigatus was abolished in FcR common γ chain-deficient mice. Thus, the opsonic and antifungal activity of PTX3 is at the crossroad between complement, complement receptor 3-, and FcγR-mediated recognition. Because short pentraxins (eg, C-reactive protein) interact with complement and FcγR, the present results may have general significance for the mode of action of these components of the humoral arm of innate immunity.

scholarly journals Complement Receptor 3 Blockade Promotes IL-12-Mediated Clearance ofPorphyromonas gingivalisand Negates Its Virulence In Vivo

2007 ◽  
Vol 179 (4) ◽  
pp. 2359-2367 ◽  
Author(s):  
George Hajishengallis ◽  
Muhamad-Ali K. Shakhatreh ◽  
Min Wang ◽  
Shuang Liang
Keyword(s):  
Complement Receptor ◽  
Complement Receptor 3

scholarly journals Methionine sulfoxide reductase A affects β-amyloid solubility and mitochondrial function in a mouse model of Alzheimer's disease

2016 ◽  
Vol 310 (6) ◽  
pp. E388-E393 ◽  
Author(s):  
Jackob Moskovitz ◽  
Fang Du ◽  
Connor F. Bowman ◽  
Shirley S. Yan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Sulfoxide Reductase A ◽  
Model Of Alzheimer’S Disease ◽  
Amyloid Aβ ◽  
Β Amyloid

Accumulation of oxidized proteins, and especially β-amyloid (Aβ), is thought to be one of the common causes of Alzheimer's disease (AD). The current studies determine the effect of an in vivo methionine sulfoxidation of Aβ through ablation of the methionine sulfoxide reductase A (MsrA) in a mouse model of AD, a mouse that overexpresses amyloid precursor protein (APP) and Aβ in neurons. Lack of MsrA fosters the formation of methionine sulfoxide in proteins, and thus its ablation in the AD-mouse model will increase the formation of methionine sulfoxide in Aβ. Indeed, the novel MsrA-deficient APP mice ( APP+/ MsrAKO) exhibited higher levels of soluble Aβ in brain compared with APP+ mice. Furthermore, mitochondrial respiration and the activity of cytochrome c oxidase were compromised in the APP+/ MsrAKO compared with control mice. These results suggest that lower MsrA activity modifies Aβ solubility properties and causes mitochondrial dysfunction, and augmenting its activity may be beneficial in delaying AD progression.

scholarly journals The Molecular Mechanism of Chronic High-Dose Corticosterone-Induced Aggravation of Cognitive Impairment in APP/PS1 Transgenic Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Shen-Qing Zhang ◽  
Long-Long Cao ◽  
Yun-Yue Liang ◽  
Pu Wang
Keyword(s):  
Preclinical Model ◽  
High Dose ◽  
Term Administration ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Stimulation Of ◽  
Bace 1

Clinical studies have found that some Alzheimer’s disease (AD) patients suffer from Cushing’s syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of β-amyloid (Aβ). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 in in vitro and in vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1 via the PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons.

scholarly journals Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer’s mouse model

2016 ◽  
Vol 213 (5) ◽  
pp. 677-685 ◽  
Author(s):  
Carla M. Yuede ◽  
Hyo Lee ◽  
Jessica L. Restivo ◽  
Todd A. Davis ◽  
Jane C. Hettinger ◽  
...  
Keyword(s):  
Human Studies ◽  
In Vivo Measurement ◽  
Significant Prolongation ◽  
Secretase Inhibitor ◽  
Electrochemical Approach ◽  
Key Factor ◽  
Β Amyloid ◽  
Aβ Clearance ◽  
Clearance Kinetics

Findings from genetic, animal model, and human studies support the observation that accumulation of the β-amyloid (Aβ) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer’s disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aβ clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aβ clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aβ levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aβ levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aβ40 in the ISF are relatively stable and begin to decline within minutes of blocking Aβ production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood–brain barrier transport of Aβ, resulted in significant prolongation of Aβ40 half-life, but only in the latter phase of Aβ clearance from the ISF.

scholarly journals Fimbrial Proteins ofPorphyromonas gingivalisMediate In Vivo Virulence and Exploit TLR2 and Complement Receptor 3 to Persist in Macrophages

2007 ◽  
Vol 179 (4) ◽  
pp. 2349-2358 ◽  
Author(s):  
Min Wang ◽  
Muhamad-Ali K. Shakhatreh ◽  
Deanna James ◽  
Shuang Liang ◽  
So-ichiro Nishiyama ◽  
...  
Keyword(s):  
Complement Receptor ◽  
Complement Receptor 3

scholarly journals Microglia modulation with 1070-nm light attenuates Aβ burden and cognitive impairment in Alzheimer’s disease mouse model

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Lechan Tao ◽  
Qi Liu ◽  
Fuli Zhang ◽  
Yuting Fu ◽  
Xi Zhu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Near Infrared ◽  
Biological Responses ◽  
Near Infrared Spectra ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Aβ Clearance ◽  
Ad Mouse Model

AbstractPhotobiomodulation, by utilizing low-power light in the visible and near-infrared spectra to trigger biological responses in cells and tissues, has been considered as a possible therapeutic strategy for Alzheimer’s disease (AD), while its specific mechanisms have remained elusive. Here, we demonstrate that cognitive and memory impairment in an AD mouse model can be ameliorated by 1070-nm light via reducing cerebral β-amyloid (Aβ) burden, the hallmark of AD. The glial cells, including microglia and astrocytes, play important roles in Aβ clearance. Our results show that 1070-nm light pulsed at 10 Hz triggers microglia rather than astrocyte responses in AD mice. The 1070-nm light-induced microglia responses with alteration in morphology and increased colocalization with Aβ are sufficient to reduce Aβ load in AD mice. Moreover, 1070-nm light pulsed at 10 Hz can reduce perivascular microglia and promote angiogenesis to further enhance Aβ clearance. Our study confirms the important roles of microglia and cerebral vessels in the use of 1070-nm light for the treatment of AD mice and provides a framework for developing a novel therapeutic approach for AD.

scholarly journals 17β-Estradiol and Progesterone Regulate Expression of β-Amyloid Clearance Factors in Primary Neuron Cultures and Female Rat Brain

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5467-5479 ◽  
Author(s):  
Anusha Jayaraman ◽  
Jenna C. Carroll ◽  
Todd E. Morgan ◽  
Sharon Lin ◽  
Liqin Zhao ◽  
...  
Keyword(s):  
Sex Steroid ◽  
Female Rat ◽  
Converting Enzyme ◽  
Primary Neuron ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
17Β Estradiol ◽  
Β Amyloid ◽  
Aβ Clearance

Abstract The accumulation of β-amyloid protein (Aβ) is a key risk factor in the development of Alzheimer's disease. The ovarian sex steroid hormones 17β-estradiol (E2) and progesterone (P4) have been shown to regulate Aβ accumulation, although the underlying mechanism(s) remain to be fully elucidated. In this study, we investigate the effects of E2 and P4 treatment on the expression levels of Aβ clearance factors including insulin-degrading enzyme, neprilysin, endothelin-converting enzyme 1 and 2, angiotensin-converting enzyme, and transthyretin, both in primary neuron cultures and female rat brains. Our results show that E2 and P4 affect the expression levels of several Aβ clearance factors in dose- and time-dependent manners. Most notably, expression of insulin-degrading enzyme is significantly increased by both hormones in cultured neurons and in vivo and is inversely associated with the soluble Aβ levels in vivo. These findings further define sex steroid hormone actions involved in regulation of Aβ, a relationship potentially important to therapeutic approaches aimed at reducing risk of Alzheimer's disease.

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