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Microglia alzheimer's disease

Guillermo Carbajosa, Karim Malki, Nathan Lawless, Hong Wang, John W Ryder, Eva Wozniak, Kristie Wood, Charles A Mein, Richard J B Dobson, David A Collier, Michael J O'Neill, Angela K Hodges, Stephen J Newhouse
Rare heterozygous coding variants in the triggering receptor expressed in myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell-type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity...
May 17, 2018: Neurobiology of Aging
Stefano Tarantini, M Noa Valcarcel-Ares, Andriy Yabluchanskiy, Zsuzsanna Tucsek, Peter Hertelendy, Tamas Kiss, Tripti Gautam, Xin A Zhang, William E Sonntag, Rafael de Cabo, Eszter Farkas, Michael H Elliott, Michael T Kinter, Ferenc Deak, Zoltan Ungvari, Anna Csiszar
Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment...
June 14, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
J Vérité, T Janet, D Chassaing, B Fauconneau, H Rabeony, G Page
BACKGROUND: Alzheimer's disease is widely described since the discovery of histopathological lesions in Mrs. Auguste Deter in 1906. However to date, there is no effective treatment to deal with the many cellular and molecular alterations. The complexity is even higher with the growing evidence of involvement of the peripheral blood mononuclear cells (PBMCs). Indeed, monocytes and T cells are shown in the cerebral parenchyma of AD patients, and these cells grafted to the periphery are able to go through the blood-brain barrier (BBB) in transgenic mouse models...
June 13, 2018: Journal of Neuroinflammation
Eleonora Rossi, Eva Mracsko, Adam Papadimitropoulos, Nima Allafi, Dieter Reinhardt, Arne Mehrkens, Ivan Martin, Irene Knuesel, Arnaud Scherberich
Triggering receptor expressed on myeloid cells-2 (TREM-2), a transmembrane receptor expressed by macrophages, microglia and osteoclasts, plays a protective role in late-onset Alzheimer Disease (AD). To validate TREM-2 as a therapeutic target in AD, its potential secondary effect on bone homeostasis should be clarified. However, animal models and monolayer cultures of human cells were shown poorly predictive of TREM-2 function in human. Therefore, this study aimed to engineer a tridimensional in vitro model using human progenitors differentiated into osteoblasts and osteoclasts, recapitulating physiological bone homeostasis...
June 13, 2018: Tissue Engineering. Part C, Methods
Yali Chen, Mengmei Yin, Xuejin Cao, Gang Hu, Ming Xiao
Both hypercholesterolemia and aging are related to cognitive decline or Alzheimer's disease. However, their interactive influence on the neurodegenerative progress remains unclear. To address this issue, 6-month-old and 16-month-old female mice were fed a 3% cholesterol diet for 8 weeks, followed by hippocampus-related functional, pathological, biochemical and molecular analyses. The high cholesterol diet did not exacerbate age-dependent cognitive decline and hippocampal neuronal death, and even greatly mitigated decreases of synaptophysin and growth associated protein 43 expression in the hippocampus of aged mice...
June 2018: Aging and Disease
Matthew J Huentelman, Ignazio S Piras, Ashley L Siniard, Matthew D De Both, Ryan F Richholt, Chris D Balak, Pouya Jamshidi, Eileen H Bigio, Sandra Weintraub, Emmaleigh T Loyer, M-Marsel Mesulam, Changiz Geula, Emily J Rogalski
Introduction : SuperAgers are adults age 80+ with episodic memory performance that is at least as good as that of average middle-aged adults. Understanding the biological determinants of SuperAging may have relevance to preventing age-related cognitive decline and dementia. This study aimed to identify associations between genetic variations and the SuperAging phenotype using Whole Exome Sequencing (WES). Methods : Sequence Kernel Association Combined (SKAT-C) test was conducted at the gene level including both rare and common variants in 56 SuperAgers and 22 cognitively-average controls from the Alzheimer's disease Neuroimaging Initiative (ADNI)...
2018: Frontiers in Aging Neuroscience
Brahim Gargouri, Johanna Carstensen, Harsharan S Bhatia, Michael Huell, Gunnar P H Dietz, Bernd L Fiebich
BACKGROUND: Neuroinflammation is a key factor of Alzheimer's disease (AD) and other neurodegenerative conditions. Microglia are the resident mononuclear immune cells of the central nervous system (CNS). They play an essential role in the maintenance of homeostasis and responses to neuroinflammation. Ginkgo biloba extract EGb 761 is one of the most commonly used natural medicines owing to its established efficacy and remarkable biological activities especially in respect to CNS diseases...
May 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Seung Pil Yun, Tae-In Kam, Nikhil Panicker, SangMin Kim, Yumin Oh, Jong-Sung Park, Seung-Hwan Kwon, Yong Joo Park, Senthilkumar S Karuppagounder, Hyejin Park, Sangjune Kim, Nayeon Oh, Nayoung Alice Kim, Saebom Lee, Saurav Brahmachari, Xiaobo Mao, Jun Hee Lee, Manoj Kumar, Daniel An, Sung-Ung Kang, Yunjong Lee, Kang Choon Lee, Dong Hee Na, Donghoon Kim, Sang Hun Lee, Viktor V Roschke, Shane A Liddelow, Zoltan Mari, Ben A Barres, Valina L Dawson, Seulki Lee, Ted M Dawson, Han Seok Ko
Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases1,2 . Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer's disease and Parkinson's disease3-13 ...
June 11, 2018: Nature Medicine
Ji Wang, Hongyi Xing, Lin Wan, Xingjun Jiang, Chen Wang, Yan Wu
As the first line of defense in the nervous system, resident microglia are the predominant immune cells in the brain. In diseases of the central nervous system such as stroke, Alzheimer's disease, and Parkinson's disease, they often cause inflammation or phagocytosis; however, some studies have found that despite the current controversy over M1, M2 polarization could be beneficial. Ischemic stroke is the third most common cause of death in humans. Patients who survive an ischemic stroke might experience a clear decline in their quality of life, owing to conditions such as hemiplegic paralysis and aphasia...
June 5, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Alfonso Grimaldi, Carlo Brighi, Giovanna Peruzzi, Davide Ragozzino, Valentina Bonanni, Cristina Limatola, Giancarlo Ruocco, Silvia Di Angelantonio
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the pathogenesis of AD a pivotal role is played by two neurotoxic proteins that aggregate and accumulate in the central nervous system: amyloid beta and hyper-phosphorylated tau. Accumulation of extracellular amyloid beta plaques and intracellular hyper-phosphorylated tau tangles, and consequent neuronal loss begins 10-15 years before any cognitive impairment. In addition to cognitive and behavioral deficits, sensorial abnormalities have been described in AD patients and in some AD transgenic mouse models...
June 7, 2018: Cell Death & Disease
Irene Reyes-Resina, Gemma Navarro, David Aguinaga, Enric I Canela, Clara T Schoeder, Michal Zaluski, Katarzyna Kiec-Kononowicz, Carlos A Saura, Christa E Müller, Rafael Franco
GPR18, still considered an orphan receptor, may respond to endocannabinoids, whose canonical receptors are CB1 and CB2 . GPR18 and CB2 receptors share a role in peripheral immune response regulation and are co-expressed in microglia, which are immunocompetent cells in the central nervous system (CNS). We aimed at identifying heteroreceptor complexes formed by GPR18 and CB1 R or CB2 R in resting and activated microglia. Receptor-receptor interaction was assessed using energy-transfer approaches, and receptor function by determining cAMP levels and ERK1/2 phosphorylation in heterologous cells and primary cultures of microglia...
June 2, 2018: Biochemical Pharmacology
Jie Feng, Jingxue Wang, Yehong Du, Ying Liu, Wei Zhang, Jingfei Chen, Yuanjie Liu, Min Zheng, Kejian Wang, Guiqiong He
BACKGROUND: Activated microglia-mediated inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). In addition, chronic activation of NLRP3 inflammasomes triggered by amyloid β peptide (Aβ) in microglia contributes to persistent neuroinflammation. Here, the primary goal was to assess whether Dihydromyricetin (DHM), a plant flavonoid compound, is effective therapies for AD; it is crucial to know whether DHM will affect microglial activation and neuroinflammation in APP/PS1 transgenic mice...
June 4, 2018: CNS Neuroscience & Therapeutics
Hye-Sun Lim, Yu Jin Kim, Bu-Yeo Kim, Gunhyuk Park, Soo-Jin Jeong
The activation of microglia is decisively involved with the neurodegeneration observed in many neuroinflammatory pathologies, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Tectorigenin (TEC) is an isoflavone isolated from various medicinal plants, such as Pueraria thunbergiana Benth, Belamcanda chinensis , and Iris unguicularis . In the present study, the neuroinflammatory effects of TEC were evaluated in both lipopolysaccharide (LPS)-treated BV-2 microglial and mouse models. TEC remarkably inhibited reactive oxygen species (ROS) generation...
2018: Frontiers in Pharmacology
Victoria Navarro, Elisabeth Sanchez-Mejias, Sebastian Jimenez, Clara Muñoz-Castro, Raquel Sanchez-Varo, Jose C Davila, Marisa Vizuete, Antonia Gutierrez, Javier Vitorica
Microglial activation has been considered a crucial player in the pathological process of multiple human neurodegenerative diseases. In some of these pathologies, such as Amyotrophic Lateral Sclerosis or Multiple Sclerosis, the immune system and microglial cells (as part of the cerebral immunity) play a central role. In other degenerative processes, such as Alzheimer's disease (AD), the role of microglia is far to be elucidated. In this "mini-review" article, we briefly highlight our recent data comparing the microglial response between amyloidogenic transgenic models, such as APP/PS1 and AD patients...
2018: Frontiers in Aging Neuroscience
Anne-Caroline Schmöle, Ramona Lundt, Gregor Toporowski, Jan N Hansen, Eva Beins, Annett Halle, Andreas Zimmer
It is widely accepted that the endocannabinoid system (ECS) is a modulator of neuroinflammation associated with neurodegenerative disorders, including Alzheimer's disease (AD). Thus, expression of the cannabinoid receptor 2 (CB2) is induced in plaque-associated microglia and astrocytes in brain tissues from AD patients and in genetic mouse models expressing pathogenic variants of the amyloid precursor protein (APP). However, the exact mechanism of CB2 signaling in this mouse model remains elusive, because the genetic deletion of CB2 and the pharmacological activation of CB2 both reduced neuroinflammation...
May 28, 2018: Journal of Alzheimer's Disease: JAD
Zhi-Zhang Dong, Juan Li, Yi-Feng Gan, Xue-Rong Sun, Yun-Xia Leng, Jian Ge
AIM: To identify the pathological role of amyloid beta (Aβ) deposition in retinal degeneration, and explore Aβ deposition on the retinal pigment epithelium cells (RPE) layer and the associated structural and functional changes in Alzheimer's disease transgenic mice. METHODS: RPE changes in the eyes of APPswe/PS1 transgenic and none transgenic (NTG) mice over 20 months old were examined. Histological changes were investigated via hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM) examination, whereas the expression of amyloid precursor protein (APP), Aβ, Zonula occludens-1 (ZO-1) and Ionized calcium binding adaptor molecule-1 (IBA-1) were investigated using immunohistochemistry and immunofluorescence techniques...
2018: International Journal of Ophthalmology
Yuan-Ta Lin, Jinsoo Seo, Fan Gao, Heather M Feldman, Hsin-Lan Wen, Jay Penney, Hugh P Cam, Elizabeta Gjoneska, Waseem K Raja, Jemmie Cheng, Richard Rueda, Oleg Kritskiy, Fatema Abdurrob, Zhuyu Peng, Blerta Milo, Chung Jong Yu, Sara Elmsaouri, Dilip Dey, Tak Ko, Bruce A Yankner, Li-Huei Tsai
The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells)...
May 22, 2018: Neuron
Kumiko Eguchi, Tomohiko Shindo, Kenta Ito, Tsuyoshi Ogata, Ryo Kurosawa, Yuta Kagaya, Yuto Monma, Sadamitsu Ichijo, Sachie Kasukabe, Satoshi Miyata, Takeo Yoshikawa, Kazuhiko Yanai, Hirofumi Taki, Hiroshi Kanai, Noriko Osumi, Hiroaki Shimokawa
BACKGROUND: Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD), and if so, to elucidate the common underlying mechanism(s) involved. METHODS: We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model...
May 22, 2018: Brain Stimulation
Zhihao Xu, Wenbin Nan, Xiaoyue Zhang, Yuliang Sun, Jichao Yang, Kecheng Lu, Yalin Liu, Yaoxin Gao, Fen Yang, Wenchao Mao, Xuekun Xing, Jiang Du, Han Li, Yonghai Li, Huigen Feng, Zhiqing Yuan, Juntang Lin
Mesenchymal stem cell (MSC) therapy is a promising prospect for the treatment of Alzheimer's disease (AD); however, the underlying mechanisms by which MSCs mediate positive effects are still unclear. We speculated that MSCs mediate microglial autophagy and enhance the clearance of Aβ. To test this hypothesis, we cultured BV2 microglial cells with umbilical cord mesenchymal stem cells conditioned medium (ucMSCs-CM) in the presence or absence of Aβ25-35 oligomers. We investigated BV2 cell proliferation, cell death, and Aβ25-35 phagocytosis as well as protein expression levels of LC3, Beclin-1, p62, insulin-degrading enzyme (IDE), and neprilysin (Nep) with western blotting...
May 29, 2018: Journal of Molecular Neuroscience: MN
Baayla D C Boon, Jeroen J M Hoozemans, Boaz Lopuhaä, Kristel N Eigenhuis, Philip Scheltens, Wouter Kamphorst, Annemieke J M Rozemuller, Femke H Bouwman
BACKGROUND: While most patients with Alzheimer's disease (AD) present with memory complaints, 30% of patients with early disease onset present with non-amnestic symptoms. This atypical presentation is thought to be caused by a different spreading of neurofibrillary tangles (NFT) than originally proposed by Braak and Braak. Recent studies suggest a prominent role for neuroinflammation in the spreading of tau pathology. METHODS: We aimed to explore whether an atypical spreading of pathology in AD is associated with an atypical distribution of neuroinflammation...
May 29, 2018: Journal of Neuroinflammation
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