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Astrocyte ApoE microglia

Laia Montoliu-Gaya, Sandra D Mulder, Maaike A C Herrebout, Johannes C Baayen, Sandra Villegas, Robert Veerhuis
An imbalance between production and clearance of soluble amyloid-β (Aβ) initiates the pathological process in sporadic Alzheimer's disease (AD). Aβ-specific antibodies seemed promising as therapeutic option in AD mouse models. In patients, however, vascular side-effects and Aβ-antibody complex-induced microglial and/or perivascular macrophage inflammatory responses were encountered. To prevent inflammatory reactions, we designed a single chain variable fragment (scFv-h3D6), based on monoclonal antibody bapineuzumab (mAb-h3D6), but lacking the Fc region...
April 3, 2018: Molecular and Cellular Neurosciences
Jianjia Fan, Rui Qi Zhao, Cameron Parro, Wenchen Zhao, Hsien-Ya Chou, Jerome Robert, Tarek Z Deeb, Carina Raynoschek, Samantha Barichievy, Ola Engvist, Marcello Maresca, Ryan Hicks, Johan Meuller, Stephen J Moss, Nicholas J Brandon, Michael W Wood, Iva Kulic, Cheryl L Wellington
Apolipoprotein E (apoE) is the primary lipid carrier within the central nervous system (CNS) and the strongest genetic risk factor for late onset Alzheimer's disease (AD). ApoE is primarily lipidated via the ATP-binding cassette transporter 1 (ABCA1), and both are under transcriptional regulation by the liver X nuclear receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden...
March 21, 2018: Journal of Lipid Research
Massimo Barbierato, Mila Borri, Laura Facci, Morena Zusso, Stephen D Skaper, Pietro Giusti
Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-α and lipopolysaccaride (LPS)...
September 22, 2017: Scientific Reports
Irena Lavrnja, Kosara Smiljanic, Danijela Savic, Aleksandra Mladenovic-Djordjevic, Katarina Tesovic, Selma Kanazir, Sanja Pekovic
Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease...
June 2, 2017: Scientific Reports
Patrick C G Haddick, Jessica L Larson, Nisha Rathore, Tushar R Bhangale, Qui T Phung, Karpagam Srinivasan, David V Hansen, Jennie R Lill, Margaret A Pericak-Vance, Jonathan Haines, Lindsay A Farrer, John S Kauwe, Gerard D Schellenberg, Carlos Cruchaga, Alison M Goate, Timothy W Behrens, Ryan J Watts, Robert R Graham, Joshua S Kaminker, Marcel van der Brug
The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner...
2017: Journal of Alzheimer's Disease: JAD
Adrián G Sandoval-Hernández, Alejandro Restrepo, Gloria P Cardona-Gómez, Gonzalo Arboleda
The vascular hypothesis of Alzheimer's disease postulates that disruption of the brain microvasculature is important for the accumulation of amyloid beta and increased neuroinflammation. Liver X Receptor agonist, GW3965, has been demonstrated to successfully modulate neuroinflammation and lipid metabolism in murine models of AD. This is partially due to increased expression of ApoE levels and increased mobility of endothelial progenitor cells. This paper analyzes changes in the neurovascular unit and in astrocytes and microglia markers following oral administration of GW3965 in a very old triple transgenic AD mice (3xTg-AD mice)...
May 16, 2016: Neuroscience Letters
Alberto Serrano-Pozo, Rebecca A Betensky, Matthew P Frosch, Bradley T Hyman
Amyloid (senile) plaques, one of the two pathologic hallmarks of Alzheimer disease (AD), are associated with dystrophic neurites and glial responses, both astrocytic and microglial. Although plaque burden remains relatively stable through the clinical course of AD, whether these features of local plaque toxicity continue to worsen over the course of the disease is unclear. We performed an unbiased plaque-centered quantification of SMI312(+) dystrophic neurites, GFAP(+) reactive astrocytes, and IBA1(+) and CD68(+) activated microglia in randomly selected dense-core (Thioflavin-S(+)) plaques from the temporal neocortex of 40 AD subjects with a symptom duration ranging from 4 to 20 years, and nine nondemented control subjects with dense-core plaques...
February 2016: American Journal of Pathology
Ileana Soto, Leah C Graham, Hannah J Richter, Stephen N Simeone, Jake E Radell, Weronika Grabowska, W Keith Funkhouser, Megan C Howell, Gareth R Howell
Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes...
October 2015: PLoS Biology
Asad Jan, Joanna M Karasinska, Martin H Kang, Willeke de Haan, Piers Ruddle, Achint Kaur, Colum Connolly, Blair R Leavitt, Poul H Sorensen, Michael R Hayden
The ATP-binding cassette transporter A1 (ABCA1) is a membrane bound protein that serves to efflux cholesterol and phospholipids onto lipid poor apolipoproteins during HDL biogenesis. Increasing the expression and activity of ABCA1 have beneficial effects in experimental models of various neurologic and cardiovascular diseases including Alzheimer's disease. Despite the beneficial effects of liver X receptor (LXR) agonists--compounds that increase ABCA1 expression--in preclinical studies, their therapeutic utility is limited by systemic adverse effects on lipid metabolism...
June 26, 2015: Neuroscience Letters
Yimei Liu, Xiaohua Xu, Hongbo Dou, Ying Hua, Jinwen Xu, Xu Hui
More and more evidences suggestted that ApoE plays an important role in modulating the systemic and central nervous inflammatory responses. However, there is a lack of exacted mechanism of ApoE. In this study, we aimed to investigate whether apolipoprotein E (ApoE) induced inflammatory responses and apoptosis in neonatal mice brain from ApoE deficient (ApoE(-/-)) and wildtype (WT). Compared to control group, the microglia cell from ApoE(-/-) mice showed more severe inflammation and cell death such as iNOS and IL-1β...
2015: International Journal of Clinical and Experimental Medicine
Sophie Stukas, Jerome Robert, Michael Lee, Iva Kulic, Michael Carr, Katherine Tourigny, Jianjia Fan, Dhananjay Namjoshi, Kalistyne Lemke, Nicole DeValle, Jeniffer Chan, Tammy Wilson, Anna Wilkinson, Rafi Chapanian, Jayachandran N Kizhakkedathu, John R Cirrito, Michael N Oda, Cheryl L Wellington
BACKGROUND: Brain lipoprotein metabolism is dependent on lipoprotein particles that resemble plasma high-density lipoproteins but that contain apolipoprotein (apo) E rather than apoA-I as their primary protein component. Astrocytes and microglia secrete apoE but not apoA-I; however, apoA-I is detectable in both cerebrospinal fluid and brain tissue lysates. The route by which plasma apoA-I enters the central nervous system is unknown. METHODS AND RESULTS: Steady-state levels of murine apoA-I in cerebrospinal fluid and interstitial fluid are 0...
December 2014: Journal of the American Heart Association
Wenjuan Zhao, Jiguo Zhang, Elizabeth G Davis, G William Rebeck
We used a lentiviral system for expressing secreted human Aβ in the brains of young and old APOE knock-in mice. This system allowed us to examine Aβ metabolism in vivo, and test the effects of both aging and APOE genotype, two of the strongest risk factors for Alzheimer's disease. We injected the Aβ1-42 lentivirus into the motor cortex of young (2 month old) and old (20-22 month old) APOE3 and APOE4 mice. After 2 weeks of lentiviral expression, we analyzed the pattern of Aβ accumulation, glial activation, and phosphor-tau...
2014: Frontiers in Aging Neuroscience
Eiron Cudaback, Yue Yang, Thomas J Montine, C Dirk Keene
Apolipoprotein E (apoE) is well known as a regulator of cholesterol homeostasis, and is increasingly recognized to play a prominent role in the modulation of innate immune response, including cell-to-cell communication and migration. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder characterized by neuroinflammation that appears to be an important component of the pathophysiology of the disease. Astrocytes are the majority cell type in brain, exerting significant influence over a range of central nervous system activities, including microglial-mediated neuroinflammatory responses...
January 2015: Glia
Gustavo A Rodriguez, Leon M Tai, Mary Jo LaDu, G William Rebeck
BACKGROUND: Having the apolipoprotein E4 (APOE-ϵ4) allele is the strongest genetic risk factor for the development of Alzheimer's disease (AD). Accumulation of amyloid beta (Aβ) in the brain is influenced by APOE genotype. Transgenic mice co-expressing five familial AD mutations (5xFAD) in the presence of human APOE alleles (ϵ2, ϵ3 or ϵ4) exhibit APOE genotype-specific differences in early Aβ accumulation, suggesting an interaction between APOE and AD pathology. Whether APOE genotype affects Aβ-plaque-associated neuroinflammation remains unclear...
2014: Journal of Neuroinflammation
Xin Yan, Fan Yang, Jan Lukas, Martin Witt, Andreas Wree, Arndt Rolfs, Jiankai Luo
Niemann-Pick disease type C1 (NPC1) is a neurodegenerative disease with various progressive pathological features, for example, neuronal loss, dysmyelination, abnormal axon swelling, and gliosis, in the brain. Pathological activation of p38-mitogen-activated protein kinase (MAPK) results in hyperphosphorylation of tau protein, which contributes to the development of neurodegenerative diseases. In this study, axonal varicosities or spheroids and presynaptic aggregates in the spinal cord of the Npc1 mutant mice were found from postnatal day (P) 35 onwards, as indicated by the increased hyperphosphorylated neurofilament and synaptophysin immunoreactivity as well as the findings from electron microscopy...
July 2014: Glia
Rupinder K Sodhi, Nirmal Singh
Vitamin A and its derivatives, the retinoids, modulate several physiological and pathological processes through their interactions with nuclear retinoid receptor proteins termed as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). An increasing body of evidence signifies the existence of retinoid signaling in diverse brain areas including cortex, amygdala, hypothalamus, hippocampus, and striatum suggesting its involvement in adult brain functions. Defective retinoid signaling has been evidenced in the pathology of Alzheimer's disease...
May 2014: Pharmacology, Biochemistry, and Behavior
Sandra D Mulder, Henrietta M Nielsen, Marinus A Blankenstein, Piet Eikelenboom, Robert Veerhuis
Defective clearance of the amyloid-β peptide (Aβ) from the brain is considered a strong promoter in Alzheimer's disease (AD) pathogenesis. Astrocytes and microglia are important mediators of Aβ clearance and Aβ aggregation state and the presence of amyloid associated proteins (AAPs), such as Apolipoproteins E and J (ApoE and ApoJ), may influence Aβ clearance by these cells. Here we set out to investigate whether astrocytes and microglia differ in uptake efficiency of Aβ oligomers (Aβoligo ) and Aβ fibrils (Aβfib ), and whether the Aβ aggregation state and/or presence of AAPs affect Aβ uptake in these cells in vitro...
April 2014: Glia
Wenjuan Zhao, Sonya B Dumanis, Irfan Y Tamboli, Gustavo A Rodriguez, Mary Jo Ladu, Charbel E H Moussa, G William Rebeck
Intraneuronal accumulation of β-amyloid (Aβ)42 is one of the earliest pathological events in humans and in animal models of Alzheimer's disease (AD). Apolipoprotein E 4 (APOE4) is the major identified genetic risk factor for late-onset AD, with Aβ deposition beginning earlier in apoE4-positive subjects. To directly determine the effects of APOE genotype on intraneuronal accumulation of Aβ1-42 at the onset of AD pathogenesis, we introduced lentiviral Aβ1-42 into the cortex of APOE targeted replacement (TR) mice at the age of 8-9 months...
March 1, 2014: Human Molecular Genetics
Shan Liu, Ariel Breitbart, Yanjie Sun, Pankaj D Mehta, Allal Boutajangout, Henrieta Scholtzova, Thomas Wisniewski
Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late-onset Alzheimer's disease (AD). Studies have shown that the binding between apoE and amyloid-β (Aβ) peptides occurs at residues 244-272 of apoE and residues 12-28 of Aβ. ApoE4 has been implicated in promoting Aβ deposition and impairing clearance of Aβ. We hypothesized that blocking the apoE/Aβ interaction would serve as an effective new approach to AD therapy. We have previously shown that treatment with Aβ12-28P can reduce amyloid plaques in APP/PS1 transgenic (Tg) mice and vascular amyloid in TgSwDI mice with congophilic amyloid angiopathy...
February 2014: Journal of Neurochemistry
Shaila P Handattu, Candyce E Monroe, Gaurav Nayyar, Mayakonda N Palgunachari, Inga Kadish, Thomas van Groen, G M Anantharamaiah, David W Garber
BACKGROUND: Apolipoprotein E (ApoE) is the major apolipoprotein present in the high-density lipoprotein-like particles in the central nervous system (CNS). ApoE is involved in various protective functions in CNS including cholesterol transport, anti-inflammatory, and antioxidant effects. An ApoE peptide would be expected to exert protective effects on neuroinflammation. OBJECTIVE: To determine the effects of an ApoE mimetic peptide Ac-hE18A-NH2 on amyloid-β pathology...
2013: Journal of Alzheimer's Disease: JAD
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