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microglia alzheimers

Chye Soi Moi, Chia Kin Yen, Khuen Yen Ng, Koh Rhun Yian
Protein misfolding and aggregation have been considered the common pathological hallmarks for a number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). These abnormal proteins aggregation damage mitochondria and induce oxidative stress and resulting neuronal cell death. Prolong neuronal damage activates microglia and astrocytes, development of inflammation reaction and further promotes neurodegeneration. Thus, elimination of abnormal proteins aggregation without eliciting any adverse effects are the main treatment strategies...
March 15, 2018: CNS & Neurological Disorders Drug Targets
Lisa K Gouwens, Mudar S Ismail, Victoria A Rogers, Nathan T Zeller, Evan C Garrad, Fatima S Amtashar, Nyasha J Makoni, David C Osborn, Michael R Nichols
Microvesicles (MVs) and exosomes comprise a class of cell-secreted particles termed extracellular vesicles (EVs). These cargo-holding vesicles mediate cell-to-cell communication and have recently been implicated in neurodegenerative diseases such as Alzheimer's disease (AD). The two types of EVs are distinguished by the mechanism of cell release and their size, with the smaller exosomes and the larger MVs ranging from 30 to 100 nm and 100 nm to 1 μm in diameter, respectively. MV numbers are increased in AD and appear to interact with amyloid-β peptide (Aβ), the primary protein component of the neuritic plaques in the AD brain...
March 15, 2018: ACS Chemical Neuroscience
Zhuo Wang, Ya-Hong Zhang, Chuang Guo, Hui-Ling Gao, Man-Li Zhong, Ting-Ting Huang, Na-Na Liu, Rui-Fang Guo, Tian Lan, Wei Zhang, Zhan-You Wang, Pu Zhao
Although the positive relationship between copper and Alzheimer's disease (AD) was reported by a lot of epidemiological data, the mechanism is not completely known. Copper is a redox metal and serves as a mediator of inflammation. Because the homeostasis of copper is altered in Aβ precursor protein (APP) and presenilin 1 (PS1) transgenic (Tg) mice, the using of copper chelators is a potential therapeutic strategy for AD. Here we report that a copper chelator, tetrathiomolybdate (TM), is a potential therapeutic drug of AD...
2018: Frontiers in Aging Neuroscience
Santa Mammana, Paolo Fagone, Eugenio Cavalli, Maria Sofia Basile, Maria Cristina Petralia, Ferdinando Nicoletti, Placido Bramanti, Emanuela Mazzon
In physiological conditions, different types of macrophages can be found within the central nervous system (CNS), i.e., microglia, meningeal macrophages, and perivascular (blood-brain barrier) and choroid plexus (blood-cerebrospinal fluid barrier) macrophages. Microglia and tissue-resident macrophages, as well as blood-borne monocytes, have different origins, as the former derive from yolk sac erythromyeloid precursors and the latter from the fetal liver or bone marrow. Accordingly, specific phenotypic patterns characterize each population...
March 13, 2018: International Journal of Molecular Sciences
Csaba Fekete, Csaba Vastagh, Ádám Dénes, Erik Hrabovszky, Gábor Nyiri, Imre Kalló, Zsolt Liposits, Miklós Sárvári
Microglia are instrumental for recognition and elimination of amyloid β1-42 oligomers (AβO), but the long-term consequences of AβO-induced inflammatory changes in the brain are unclear. Here, we explored microglial responses and transciptome-level inflammatory signatures in the rat hippocampus after chronic AβO challenge. Middle-aged Long Evans rats received intracerebroventricular infusion of AβO or vehicle for 4 weeks, followed by treatment with artificial CSF or MCC950 for the subsequent 4 weeks. AβO infusion evoked a sustained inflammatory response including activation of NF-κB, triggered microglia activation and increased the expression of pattern recognition and phagocytic receptors...
March 6, 2018: Neuroscience
C Y Daniel Lee, Anthony Daggett, Xiaofeng Gu, Lu-Lin Jiang, Peter Langfelder, Xiaoguang Li, Nan Wang, Yingjun Zhao, Chang Sin Park, Yonatan Cooper, Isabella Ferando, Istvan Mody, Giovanni Coppola, Huaxi Xu, X William Yang
Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes...
March 7, 2018: Neuron
Jodie Stephenson, Erik Nutma, Paul van der Valk, Sandra Amor
Neurodegenerative diseases, the leading cause of morbidity and disability is gaining increased attention as it imposes a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders...
March 7, 2018: Immunology
Cornelius K Donat, Nazanin Mirzaei, Sac-Pharm Tang, Paul Edison, Magdalena Sastre
Deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD) are believed to be linked to microglial activation. A hallmark of reactive microglia is the upregulation of mitochondrial translocator protein (TSPO) expression. Positron emission tomography (PET) is a nuclear imaging technique that measures the distribution of trace doses of radiolabeled compounds in the body over time. PET imaging using the 2nd generation TSPO tracer [11 C]PBR28 provides an opportunity for accurate visualization and quantification of changes in microglial density in transgenic mouse models of Alzheimer's disease (AD)...
2018: Methods in Molecular Biology
Elena Rodriguez-Vieitez, Agneta Nordberg
The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed, and how clinical trials are designed today. Alzheimer's disease (AD)-the most common neurodegenerative disorder-is characterized by a complex neuropathology involving the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells-astrocytes and microglia-and neuroinflammatory responses, leading to neurodegeneration and cognitive dysfunction...
2018: Methods in Molecular Biology
Vahid Reza Askari, Narges Fereydouni, Vafa Baradaran Rahimi, Nafiseh Askari, Amir Hossein Sahebkar, Pouria Rahmanian-Devin, Alireza Samzadeh-Kermani
BACKGROUND: Inflammation is a primary response to infection that can pathologically lead to various diseases including neurodegenerative diseases. The purpose of this study was to evaluate the effect of β-Amyrin, a naturally occurring pentacyclic triterpenoid compound, on inflammation induced by lipopolysaccharide (LPS) and interferone-γ (IFN-γ) in rat microglial cells. MATERIALS AND METHODS: Cytotoxicity of β-Amyrin (3-100) μM on microglial cells was evaluated using the MTT assay...
March 1, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Monika Plescher, Gerald Seifert, Jan Niklas Hansen, Peter Bedner, Christian Steinhäuser, Annett Halle
Microglia, the central nervous system resident innate immune cells, cluster around Aβ plaques in Alzheimer's disease (AD). The activation phenotype of these plaque-associated microglial cells, and their differences to microglia distant to Aβ plaques, are incompletely understood. We used novel three-dimensional cell analysis software to comprehensively analyze the morphological properties of microglia in the TgCRND8 mouse model of AD in spatial relation to Aβ plaques. We found strong morphological changes exclusively in plaque-associated microglia, whereas plaque-distant microglia showed only minor changes...
March 1, 2018: Glia
Justyna Sosna, Stephan Philipp, Ricardo Albay, Jorge Mauricio Reyes-Ruiz, David Baglietto-Vargas, Frank M LaFerla, Charles G Glabe
BACKGROUND: Besides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer's disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that neuritic plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or neuritic plaque maturation or both...
March 1, 2018: Molecular Neurodegeneration
Michael Fricker, Aviva M Tolkovsky, Vilmante Borutaite, Michael Coleman, Guy C Brown
Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity of adult neurons to proliferate or be replaced. The concept of cell death used to be simple as there were just two or three types, so we just had to work out which type was involved in our particular pathology and then block it. However, we now know that there are at least a dozen ways for neurons to die, that blocking a particular mechanism of cell death may not prevent the cell from dying, and that non-neuronal cells also contribute to neuronal death...
April 1, 2018: Physiological Reviews
Katherine E Tansey, Darren Cameron, Matthew J Hill
BACKGROUND: Genome-wide association studies of Alzheimer's disease (AD) have identified a number of significant risk loci, the majority of which lie in non-coding regions of the genome. The lack of causal alleles and considerable polygenicity remains a significant barrier to translation into mechanistic understanding. This includes identifying causal variants and the cell/tissue types in which they operate. A fuller understanding of the cell types and transcriptional networks involved in AD genetic risk mechanisms will provide important insights into pathogenesis...
February 26, 2018: Genome Medicine
Dénes Zádori, Gábor Veres, Levente Szalárdy, Péter Klivényi, László Vécsei
The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake...
2018: Journal of Alzheimer's Disease: JAD
Panchanan Maiti, Leela Paladugu, Gary L Dunbar
BACKGROUND: Neuroinflammation and the presence of amyloid beta protein (Aβ) and neurofibrillary tangles are key pathologies in Alzheimer's disease (AD). As a potent anti-amyloid and anti-inflammatory natural polyphenol, curcumin (Cur) could be potential therapies for AD. Unfortunately, poor solubility, instability in physiological fluids, and low bioavailability limit its clinical utility. Recently, different lipid modifications in the formulae of Cur have been developed that would enhance its therapeutic potential...
February 23, 2018: BMC Neuroscience
Gerhard Leinenga, Jürgen Götz
Deposition of amyloid-β (Aβ) peptide leads to amyloid plaques that together with tau deposits characterize the brains of patients with Alzheimer's disease (AD). In modeling this pathology, transgenic animals such as the APP23 strain, that expresses a mutant form of the amyloid precursor protein found in familial cases of AD, have been instrumental. In previous studies, we have shown that repeated treatments with ultrasound in a scanning mode (termed scanning ultrasound or SUS) were effective in removing Aβ and restoring memory functions, without the need for a therapeutic agent such as an Aβ antibody...
2018: Frontiers in Neuroscience
Namkwon Kim, Hyung-Seok Yoo, Yeon-Joo Ju, Myung Sook Oh, Kyung-Tae Lee, Kyung-Soo Inn, Nam-Jung Kim, Jong Kil Lee
Neuroinflammation is an immune response within the central nervous system against various proinflammatory stimuli. Abnormal activation of this response contributes to neurodegenerative diseases such as Parkinson disease, Alzheimer's disease, and Huntington disease. Therefore, pharmacologic modulation of abnormal neuroinflammation is thought to be a promising approach to amelioration of neurodegenerative diseases. In this study, we evaluated the synthetic flavone derivative 3',4'-dihydroxyflavone, investigating its anti-neuroinflammatory activity in BV2 microglial cells and in a mouse model...
March 1, 2018: Biomolecules & Therapeutics
Emilia Tze Ying Yeo, Kelly Wang Ling Wong, Mun Ling See, Ka Yan Wong, Sook Yee Gan, Elaine Wan Ling Chan
ETHNOPHARMACOLOGICAL RELEVANCE: Piper sarmentosum Roxb. (PS), belonging to Piperaceae family, is an edible plant with medicinal properties. It is traditionally used by the Malays to treat headache and boost memory. Pharmacological studies revealed that PS exhibits anti-inflammatory, anti-oxidant, anti-acetylcholinesterase, and anti-depressant-like effects. In view of this, the present study aimed to investigate the anti-inflammatory actions of PS and its potential neuroprotective effects against beta-amyloid (Aβ)-induced microglia-mediated neurotoxicity...
February 17, 2018: Journal of Ethnopharmacology
Jessica R Lowry, Andis Klegeris
Alzheimer's disease (AD) is one of the leading causes of dementia, and its prevalence is expected to increase dramatically due to the aging global population. Microglia-driven neuroinflammation may contribute to the progression of AD. Microglia, the immune cells of the central nervous system (CNS), become chronically activated by the pathological proteins of AD including amyloid-β peptides (Aβ). Such adversely activated microglia secrete mediators that promote inflammation and damage neurons. Cathepsins are proteases that are expressed by all brain cell types, and most of them are found both intra- and extra-cellularly...
February 15, 2018: Brain Research Bulletin
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