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Molecular Neurodegeneration

Saumi Mathews, Amanda Branch Woods, Ikumi Katano, Edward Makarov, Midhun B Thomas, Howard E Gendelman, Larisa Y Poluektova, Mamoru Ito, Santhi Gorantla
BACKGROUND: Microglia are the principal innate immune defense cells of the centeral nervous system (CNS) and the target of the human immunodeficiency virus type one (HIV-1). A complete understanding of human microglial biology and function requires the cell's presence in a brain microenvironment. Lack of relevant animal models thus far has also precluded studies of HIV-1 infection. Productive viral infection in brain occurs only in human myeloid linage microglia and perivascular macrophages and requires cells present throughout the brain...
March 5, 2019: Molecular Neurodegeneration
Tirth K Patel, LeMoyne Habimana-Griffin, Xuefeng Gao, Baogang Xu, Samuel Achilefu, Kari Alitalo, Celia A McKee, Patrick W Sheehan, Erik S Musiek, Chengjie Xiong, Dean Coble, David M Holtzman
BACKGROUND: Alzheimer's disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid-β (Aβ) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), some forms of frontotemporal dementia, and argyrophilic grain disease (AGD)...
February 27, 2019: Molecular Neurodegeneration
Korey Kam, Ankit Parekh, Ram A Sharma, Andreia Andrade, Monica Lewin, Bresne Castillo, Omonigho M Bubu, Nicholas J Chua, Margo D Miller, Anna E Mullins, Lidia Glodzik, Lisa Mosconi, Nadia Gosselin, Kulkarni Prathamesh, Zhe Chen, Kaj Blennow, Henrik Zetterberg, Nisha Bagchi, Bianca Cavedoni, David M Rapoport, Indu Ayappa, Mony J de Leon, Eva Petkova, Andrew W Varga, Ricardo S Osorio
BACKGROUND: Based on associations between sleep spindles, cognition, and sleep-dependent memory processing, here we evaluated potential relationships between levels of CSF Aβ42 , P-tau, and T-tau with sleep spindle density and other biophysical properties of sleep spindles in a sample of cognitively normal elderly individuals. METHODS: One-night in-lab nocturnal polysomnography (NPSG) and morning to early afternoon CSF collection were performed to measure CSF Aβ42 , P-tau and T-tau...
February 21, 2019: Molecular Neurodegeneration
Jeannie Chew, Casey Cook, Tania F Gendron, Karen Jansen-West, Giulia Del Rosso, Lillian M Daughrity, Monica Castanedes-Casey, Aishe Kurti, Jeannette N Stankowski, Matthew D Disney, Jeffrey D Rothstein, Dennis W Dickson, John D Fryer, Yong-Jie Zhang, Leonard Petrucelli
BACKGROUND: A G4 C2 hexanucleotide repeat expansion in the noncoding region of C9orf72 is the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). Putative disease mechanisms underlying c9FTD/ALS include toxicity from sense G4 C2 and antisense G2 C4 repeat-containing RNA, and from dipeptide repeat (DPR) proteins unconventionally translated from these RNA products. METHODS: Intracerebroventricular injections with adeno-associated virus (AAV) encoding 2 or 149 G4 C2 repeats were performed on postnatal day 0, followed by assessment of behavioral and neuropathological phenotypes...
February 15, 2019: Molecular Neurodegeneration
Leqiang Sun, Yajie Tang, Keji Yan, Jinsong Yu, Yanyan Zou, Weize Xu, Ke Xiao, Zhihui Zhang, Weiming Li, Beili Wu, Zhe Hu, Kening Chen, Zhen F Fu, Jinxia Dai, Gang Cao
BACKGROUND: Neurotropic virus-based tracers have been extensively applied in mapping and manipulation of neural circuits. However, their neurotropic and neurotoxic properties remain to be fully characterized. METHODS: Through neural circuit tracing, we systematically compared the neurotropism discrepancy among different multi-trans-synaptic and mono-synaptic retrograde viral tracers including pseudorabies virus (PRV), rabies virus (RV), and the newly engineered retro adeno-associated virus (rAAV2-retro) tracers...
February 8, 2019: Molecular Neurodegeneration
Shreaya Chakroborty, Evan S Hill, Daniel T Christian, Rosalind Helfrich, Shannon Riley, Corinne Schneider, Nicolas Kapecki, Sarah Mustaly-Kalimi, Figen A Seiler, Daniel A Peterson, Anthony R West, Barbara M Vertel, William N Frost, Grace E Stutzmann
BACKGROUND: Identifying effective strategies to prevent memory loss in AD has eluded researchers to date, and likely reflects insufficient understanding of early pathogenic mechanisms directly affecting memory encoding. As synaptic loss best correlates with memory loss in AD, refocusing efforts to identify factors driving synaptic impairments may provide the critical insight needed to advance the field. In this study, we reveal a previously undescribed cascade of events underlying pre and postsynaptic hippocampal signaling deficits linked to cognitive decline in AD...
January 22, 2019: Molecular Neurodegeneration
Pete A Williams, Catherine E Braine, Krishnakumar Kizhatil, Nicole E Foxworth, Nicholas G Tolman, Jeffrey M Harder, Rebecca A Scott, Gregory L Sousa, Alyssa Panitch, Gareth R Howell, Simon W M John
BACKGROUND: Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. Recent work in animal models suggests that a critical neuroinflammatory event damages retinal ganglion cell axons in the optic nerve head during ocular hypertensive injury. We previously demonstrated that monocyte-like cells enter the optic nerve head in an ocular hypertensive mouse model of glaucoma (DBA/2 J), but their roles, if any, in mediating axon damage remain unclear. METHODS: To understand the function of these infiltrating monocyte-like cells, we used RNA-sequencing to profile their transcriptomes...
January 22, 2019: Molecular Neurodegeneration
Tiago Fleming Outeiro, David J Koss, Daniel Erskine, Lauren Walker, Marzena Kurzawa-Akanbi, David Burn, Paul Donaghy, Christopher Morris, John-Paul Taylor, Alan Thomas, Johannes Attems, Ian McKeith
Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson's disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as disease progresses, there has been controversy about the separation of DLB from PD dementia (PDD) and consensus reports have put forward guidelines to assist clinicians in the identification and management of both syndromes...
January 21, 2019: Molecular Neurodegeneration
Anil B Mukherjee, Abhilash P Appu, Tamal Sadhukhan, Sydney Casey, Avisek Mondal, Zhongjian Zhang, Maria B Bagh
Neuronal Ceroid Lipofuscinoses (NCLs), commonly known as Batten disease, constitute a group of the most prevalent neurodegenerative lysosomal storage disorders (LSDs). Mutations in at least 13 different genes (called CLNs) cause various forms of NCLs. Clinically, the NCLs manifest early impairment of vision, progressive decline in cognitive and motor functions, seizures and a shortened lifespan. At the cellular level, all NCLs show intracellular accumulation of autofluorescent material (called ceroid) and progressive neuron loss...
January 16, 2019: Molecular Neurodegeneration
Luxi Wang, Sofia Pavlou, Xuan Du, Mohajeet Bhuckory, Heping Xu, Mei Chen
BACKGROUND: Uncontrolled microglial activation contributes to the pathogenesis of various neurodegenerative diseases. Previous studies have shown that proinflammatory microglia are powered by glycolysis, which relays on high levels of glucose uptake. This study aimed to understand how glucose uptake is facilitated in active microglia and whether microglial activation can be controlled by restricting glucose uptake. METHODS: Primary murine brain microglia, BV2 cells and the newly established microglial cell line B6M7 were treated with LPS (100 ng/ml) + IFNγ (100 ng/ml) or IL-4 (20 ng/ml) for 24 h...
January 11, 2019: Molecular Neurodegeneration
Yaping Shao, Weidong Le
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system (CNS), which affects mostly older adults. In recent years, the incidence of PD has been dramatically increasing with the aging population expanding. Due to the lack of effective biomarkers, the accurate diagnosis and precise treatment of PD are currently compromised. Notably, metabolites have been considered as the most direct reflection of the physiological and pathological conditions in individuals and represent attractive candidates to provide deep insights into disease phenotypes...
January 11, 2019: Molecular Neurodegeneration
Marc Suárez-Calvet, Estrella Morenas-Rodríguez, Gernot Kleinberger, Kai Schlepckow, Miguel Ángel Araque Caballero, Nicolai Franzmeier, Anja Capell, Katrin Fellerer, Brigitte Nuscher, Erden Eren, Johannes Levin, Yuetiva Deming, Laura Piccio, Celeste M Karch, Carlos Cruchaga, Leslie M Shaw, John Q Trojanowski, Michael Weiner, Michael Ewers, Christian Haass
BACKGROUND: TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid β-peptide (Aβ) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear...
January 10, 2019: Molecular Neurodegeneration
Gregor Bieri, Kurt M Lucin, Caitlin E O'Brien, Hui Zhang, Saul A Villeda, Tony Wyss-Coray
BACKGROUND: Neuronal cell loss contributes to the pathology of acute and chronic neurodegenerative diseases, including Alzheimer's disease (AD). It remains crucial to identify molecular mechanisms sensitizing neurons to various insults and cell death. To date, the multifunctional, autophagy-related protein Beclin 1 has been shown to be both necessary and sufficient for neuronal integrity in neurodegenerative models associated with protein aggregation. Interestingly, besides its role in cellular homeostasis, Beclin 1 has also been ascribed a role in apoptosis...
December 29, 2018: Molecular Neurodegeneration
Amanda McQuade, Morgan Coburn, Christina H Tu, Jonathan Hasselmann, Hayk Davtyan, Mathew Blurton-Jones
BACKGROUND: Microglia, the principle immune cells of the brain, play important roles in neuronal development, homeostatic function and neurodegenerative disease. Recent genetic studies have further highlighted the importance of microglia in neurodegeneration with the identification of disease risk polymorphisms in many microglial genes. To better understand the role of these genes in microglial biology and disease, we, and others, have developed methods to differentiate microglia from human induced pluripotent stem cells (iPSCs)...
December 22, 2018: Molecular Neurodegeneration
Maud Gratuze, Cheryl E G Leyns, David M Holtzman
Alzheimer's disease (AD) is the leading cause of dementia. The two histopathological markers of AD are amyloid plaques composed of the amyloid-β (Aβ) peptide, and neurofibrillary tangles of aggregated, abnormally hyperphosphorylated tau protein. The majority of AD cases are late-onset, after the age of 65, where a clear cause is still unknown. However, there are likely different multifactorial contributors including age, enviornment, biology and genetics which can increase risk for the disease. Genetic predisposition is considerable, with heritability estimates of 60-80%...
December 20, 2018: Molecular Neurodegeneration
Hong Wang, Yupeng Li, John W Ryder, Justin T Hole, Philip J Ebert, David C Airey, Hui-Rong Qian, Benjamin Logsdon, Alice Fisher, Zeshan Ahmed, Tracey K Murray, Annalisa Cavallini, Suchira Bose, Brian J Eastwood, David A Collier, Jeffrey L Dage, Bradley B Miller, Kalpana M Merchant, Michael J O'Neill, Ronald B Demattos
BACKGROUND: Activation of microglia, the resident immune cells of the central nervous system, is a prominent pathological hallmark of Alzheimer's disease (AD). However, the gene expression changes underlying microglia activation in response to tau pathology remain elusive. Furthermore, it is not clear how murine gene expression changes relate to human gene expression networks. METHODS: Microglia cells were isolated from rTg4510 tau transgenic mice and gene expression was profiled using RNA sequencing...
December 17, 2018: Molecular Neurodegeneration
Jiqing Cao, Jianwei Hou, Jing Ping, Dongming Cai
Alzheimer's Disease (AD), the most prevalent neurodegenerative disease of aging, affects one in eight older Americans. Nearly all drug treatments tested for AD today have failed to show any efficacy. There is a great need for therapies to prevent and/or slow the progression of AD. The major challenge in AD drug development is lack of clarity about the mechanisms underlying AD pathogenesis and pathophysiology. Several studies support the notion that AD is a multifactorial disease. While there is abundant evidence that amyloid plays a role in AD pathogenesis, other mechanisms have been implicated in AD such as tangle formation and spread, dysregulated protein degradation pathways, neuroinflammation, and loss of support by neurotrophic factors...
December 12, 2018: Molecular Neurodegeneration
Ali Jawaid, Romesa Khan, Magdalini Polymenidou, Paul E Schulz
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative disorders with considerable clinical, pathological and genetic overlap. Both disorders are characterized by the accumulation of pathological protein aggregates that contain a number of proteins, most notably TAR DNA binding protein 43 kDa (TDP-43). Surprisingly, recent clinical studies suggest that dyslipidemia, high body mass index, and type 2 diabetes mellitus are associated with better clinical outcomes in ALS...
December 4, 2018: Molecular Neurodegeneration
Huazhang Zhu, Weizhen Zhang, Yingying Zhao, Xingsheng Shu, Wencong Wang, Dandan Wang, Yangfan Yang, Zhijun He, Xiaomei Wang, Ying Ying
BACKGROUND: Although diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Key molecules involved in this process remain poorly defined. The microtubule-associated protein tau is a critical mediator of neurotoxicity in Alzheimer's disease (AD) and other neurodegenerative diseases...
November 22, 2018: Molecular Neurodegeneration
Aaron D Thome, Alireza Faridar, David R Beers, Jason R Thonhoff, Weihua Zhao, Shixiang Wen, Belen Pascual, Joseph C Masdeu, Stanley H Appel
BACKGROUND: Neuroinflammation is a hallmark of neurodegenerative disease and a significant component of the pathology of Alzheimer's disease (AD). Patients present with extensive microgliosis along with elevated pro-inflammatory signaling in the central nervous system and periphery. However, the role of peripheral myeloid cells in mediating and influencing AD pathogenesis remains unresolved. METHODS: Peripheral myeloid cells were isolated from peripheral blood of patients with prodromal AD (n = 44), mild AD dementia (n = 25), moderate/severe AD dementia (n = 28), and age-matched controls (n = 54)...
November 13, 2018: Molecular Neurodegeneration
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