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Molecular Neurodegeneration

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https://www.readbyqxmd.com/read/29017573/gad67-haploinsufficiency-reduces-amyloid-pathology-and-rescues-olfactory-memory-deficits-in-a-mouse-model-of-alzheimer-s-disease
#1
Yue Wang, Zheng Wu, Yu-Ting Bai, Gang-Yi Wu, Gong Chen
BACKGROUND: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, affecting millions of people worldwide. Although dysfunction of multiple neurotransmitter systems including cholinergic, glutamatergic and GABAergic systems has been associated with AD progression the underlying mechanisms remain elusive. We and others have recently found that GABA content is elevated in AD brains and linked to cognitive deficits in AD mouse models. The glutamic acid decarboxylase 67 (GAD67) is the major enzyme converting glutamate into GABA and has been implied in a number of neurological disorders such as epilepsy and schizophrenia...
October 10, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28978354/the-cns-in-inbred-transgenic-models-of-4-repeat-tauopathy-develops-consistent-tau-seeding-capacity-yet-focal-and-diverse-patterns-of-protein-deposition
#2
Ghazaleh Eskandari-Sedighi, Nathalie Daude, Hristina Gapeshina, David W Sanders, Razieh Kamali-Jamil, Jing Yang, Beipei Shi, Holger Wille, Bernardino Ghetti, Marc I Diamond, Christopher Janus, David Westaway
BACKGROUND: MAPT mutations cause neurodegenerative diseases such as frontotemporal dementia but, strikingly, patients with the same mutation may have different clinical phenotypes. METHODS: Given heterogeneities observed in a transgenic (Tg) mouse line expressing low levels of human (2 N, 4R) P301L Tau, we backcrossed founder stocks of mice to C57BL/6Tac, 129/SvEvTac and FVB/NJ inbred backgrounds to discern the role of genetic versus environmental effects on disease-related phenotypes...
October 4, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28969695/together-jun-and-ddit3-chop-control-retinal-ganglion-cell-death-after-axonal-injury
#3
Stephanie B Syc-Mazurek, Kimberly A Fernandes, Michael P Wilson, Peter Shrager, Richard T Libby
BACKGROUND: Optic nerve injury is an important pathological component in neurodegenerative diseases such as traumatic optic neuropathies and glaucoma. The molecular signaling pathway(s) critical for retinal ganglion cell (RGC) death after axonal insult, however, is/are not fully defined. RGC death after axonal injury is known to occur by BAX-dependent apoptosis. Two transcription factors JUN (the canonical target of JNK) and DDIT3 (CHOP; a key mediator of the endoplasmic reticulum stress response) are known to be important apoptotic signaling molecules after axonal injury, including in RGCs...
October 2, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28962651/hexokinases-link-dj-1-to-the-pink1-parkin-pathway
#4
David N Hauser, Adamantios Mamais, Melissa M Conti, Christopher T Primiani, Ravindran Kumaran, Allissa A Dillman, Rebekah G Langston, Alexandra Beilina, Joseph H Garcia, Alberto Diaz-Ruiz, Michel Bernier, Fabienne C Fiesel, Xu Hou, Wolfdieter Springer, Yan Li, Rafael de Cabo, Mark R Cookson
BACKGROUND: Early onset Parkinson's disease is caused by variants in PINK1, parkin, and DJ-1. PINK1 and parkin operate in pathways that preserve mitochondrial integrity, but the function of DJ-1 and how it relates to PINK1 and parkin is poorly understood. METHODS: A series of unbiased high-content screens were used to analyze changes at the protein, RNA, and metabolite level in rodent brains lacking DJ-1. Results were validated using targeted approaches, and cellular assays were performed to probe the mechanisms involved...
September 29, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28934974/blood-hemoglobin-a1c-levels-and-amyotrophic-lateral-sclerosis-survival
#5
Qian-Qian Wei, Yongping Chen, Bei Cao, Ru Wei Ou, Lingyu Zhang, Yanbing Hou, Xiang Gao, Huifang Shang
BACKGROUND: There are inconsistences regarding the correlation between diabetes or fasting blood glucose concentrations and the risk and survival of amyotrophic lateral sclerosis (ALS) in the previous studies. Moreover, the association between hemoglobin A1c (HbA1c) levels, which reflect long-term glycemic status, and ALS survival was not examined. METHODS: A prospective cohort study including 450 Chinese sporadic ALS patients (254 men and 196 women; mean age: 55...
September 21, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28927431/role-of-the-sigma-1-receptor-chaperone-in-rod-and-cone-photoreceptor-degenerations-in-a-mouse-model-of-retinitis-pigmentosa
#6
Huan Yang, Yingmei Fu, Xinying Liu, Pawan K Shahi, Timur A Mavlyutov, Jun Li, Annie Yao, Steven Z-W Guo, Bikash R Pattnaik, Lian-Wang Guo
BACKGROUND: Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease yet with no effective treatment available. The sigma-1 receptor (S1R), a ligand-regulated chaperone, emerges as a potential retina-protective therapeutic target. In particular, pharmacological activation of S1R was recently shown to rescue cones in the rd10 mouse, a rod Pde6b mutant that recapitulates the RP pathology of autonomous rod degeneration followed by secondary death of cones. The mechanisms underlying the S1R protection for cones are not understood in detail...
September 19, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28923099/whole-blood-gene-expression-and-white-matter-hyperintensities
#7
Honghuang Lin, Claudia Satizabal, Zhijun Xie, Qiong Yang, Tianxiao Huan, Roby Joehanes, Chengping Wen, Peter J Munson, Alexa Beiser, Daniel Levy, Sudha Seshadri
BACKGROUND: White matter hyperintensities (WMH) are an important biomarker of cumulative vascular brain injury and have been associated with cognitive decline and an increased risk of dementia, stroke, depression, and gait impairments. The pathogenesis of white matter lesions however, remains uncertain. The characterization of gene expression profiles associated with WMH might help uncover molecular mechanisms underlying WMH. METHODS: We performed a transcriptome-wide association study of gene expression profiles with WMH in 3248 participants from the Framingham Heart Study using the Affymetrix Human Exon 1...
September 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28923083/prevention-of-c5ar1-signaling-delays-microglial-inflammatory-polarization-favors-clearance-pathways-and-suppresses-cognitive-loss
#8
Michael X Hernandez, Shan Jiang, Tracy A Cole, Shu-Hui Chu, Maria I Fonseca, Melody J Fang, Lindsay A Hohsfield, Maria D Torres, Kim N Green, Rick A Wetsel, Ali Mortazavi, Andrea J Tenner
BACKGROUND: Pharmacologic inhibition of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppressed pathology and cognitive deficits in Alzheimer's disease (AD) mouse models. To validate that the effect of the antagonist was specifically via C5aR1 inhibition, mice lacking C5aR1 were generated and compared in behavior and pathology. In addition, since C5aR1 is primarily expressed on cells of the myeloid lineage, and only to a lesser extent on endothelial cells and neurons in brain, gene expression in microglia isolated from adult brain at multiple ages was compared across all genotypes...
September 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28923065/the-heat-shock-response-in-neurons-and-astroglia-and-its-role-in-neurodegenerative-diseases
#9
REVIEW
Rebecca San Gil, Lezanne Ooi, Justin J Yerbury, Heath Ecroyd
Protein inclusions are a predominant molecular pathology found in numerous neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease. Protein inclusions form in discrete areas of the brain characteristic to the type of neurodegenerative disease, and coincide with the death of neurons in that region (e.g. spinal cord motor neurons in amyotrophic lateral sclerosis). This suggests that the process of protein misfolding leading to inclusion formation is neurotoxic, and that cell-autonomous and non-cell autonomous mechanisms that maintain protein homeostasis (proteostasis) can, at times, be insufficient to prevent protein inclusion formation in the central nervous system...
September 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28886753/depletion-of-adult-neurogenesis-exacerbates-cognitive-deficits-in-alzheimer-s-disease-by-compromising-hippocampal-inhibition
#10
Carolyn Hollands, Matthew Kyle Tobin, Michael Hsu, Kianna Musaraca, Tzong-Shiue Yu, Rachana Mishra, Steven G Kernie, Orly Lazarov
BACKGROUND: The molecular mechanism underlying progressive memory loss in Alzheimer's disease is poorly understood. Neurogenesis in the adult hippocampus is a dynamic process that continuously changes the dentate gyrus and is important for hippocampal plasticity, learning and memory. However, whether impairments in neurogenesis affect the hippocampal circuitry in a way that leads to memory deficits characteristic of Alzheimer's disease is unknown. Controversial results in that regard were reported in transgenic mouse models of amyloidosis...
September 8, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28866979/quantification-of-plasma-phosphorylated-tau-to-use-as-a-biomarker-for-brain-alzheimer-pathology-pilot-case-control-studies-including-patients-with-alzheimer-s-disease-and-down-syndrome
#11
Harutsugu Tatebe, Takashi Kasai, Takuma Ohmichi, Yusuke Kishi, Tomoshi Kakeya, Masaaki Waragai, Masaki Kondo, David Allsop, Takahiko Tokuda
BACKGROUND: There is still a substantial unmet need for less invasive and lower-cost blood-based biomarkers to detect brain Alzheimer's disease (AD) pathology. This study is aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181) is informative in the diagnosis of AD. METHODS: We have developed a novel ultrasensitive immunoassay to quantify plasma p-tau181, and measured the levels of plasma p-tau181 in three cohorts. RESULTS: In the first cohort composed of 20 AD patients and 15 age-matched controls, the plasma levels of p-tau181 were significantly higher in the AD patients than those in the controls (0...
September 4, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28835281/lysosomal-processing-of-progranulin
#12
Xiaolai Zhou, Daniel H Paushter, Tuancheng Feng, Lirong Sun, Thomas Reinheckel, Fenghua Hu
BACKGROUND: Mutations resulting in progranulin (PGRN) haploinsufficiency cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. PGRN is localized to the lysosome and important for proper lysosome function. However, the metabolism of PGRN in the lysosome is still unclear. RESULTS: Here, we report that PGRN is processed into ~10 kDa peptides intracellularly in multiple cell types and tissues and this processing is dependent on lysosomal activities...
August 23, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28835279/a%C3%AE-accumulation-causes-mvb-enlargement-and-is-modelled-by-dominant-negative-vps4a
#13
Katarina Willén, James R Edgar, Takafumi Hasegawa, Nobuyuki Tanaka, Clare E Futter, Gunnar K Gouras
BACKGROUND: Alzheimer's disease (AD)-linked β-amyloid (Aβ) accumulates in multivesicular bodies (MVBs) with the onset of AD pathogenesis. Alterations in endosomes are among the earliest changes associated with AD but the mechanism(s) that cause endosome enlargement and the effects of MVB dysfunction on Aβ accumulation and tau pathology are incompletely understood. METHODS: MVB size and Aβ fibrils in primary neurons were visualized by electron microscopy and confocal fluorescent microscopy...
August 23, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28830501/high-density-lipoproteins-suppress-a%C3%AE-induced-pbmc-adhesion-to-human-endothelial-cells-in-bioengineered-vessels-and-in-monoculture
#14
Jérôme Robert, Emily B Button, Sophie Stukas, Guilaine K Boyce, Ebrima Gibbs, Catherine M Cowan, Megan Gilmour, Wai Hang Cheng, Sonja K Soo, Brian Yuen, Arvin Bahrabadi, Kevin Kang, Iva Kulic, Gordon Francis, Neil Cashman, Cheryl L Wellington
BACKGROUND: Alzheimer's Disease (AD), characterized by accumulation of beta-amyloid (Aβ) plaques in the brain, can be caused by age-related failures to clear Aβ from the brain through pathways that involve the cerebrovasculature. Vascular risk factors are known to increase AD risk, but less is known about potential protective factors. We hypothesize that high-density lipoproteins (HDL) may protect against AD, as HDL have vasoprotective properties that are well described for peripheral vessels...
August 22, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28810892/absence-of-cx3cr1-impairs-the-internalization-of-tau-by-microglia
#15
Marta Bolós, María Llorens-Martín, Juan Ramón Perea, Jerónimo Jurado-Arjona, Alberto Rábano, Félix Hernández, Jesús Avila
BACKGROUND: Extracellular Tau is toxic for neighboring cells, and it contributes to the progression of AD. The CX3CL1/CX3CR1 axis is an important neuron/microglia communication mechanism. METHODS: We studied Tau clearance by microglia both in vitro (microglia primary cultures treated with Cy5-Tau, affinity chromatography to study the binding of Tau to CX3CR1, and Tau-CX3CL1 competition assays) and in vivo (stereotaxic injection of Cy5-Tau into WT and CX3CR1(-/-) mice)...
August 15, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28774322/tau-accumulation-in-the-retina-promotes-early-neuronal-dysfunction-and-precedes-brain-pathology-in-a-mouse-model-of-alzheimer-s-disease
#16
Marius Chiasseu, Luis Alarcon-Martinez, Nicolas Belforte, Heberto Quintero, Florence Dotigny, Laurie Destroismaisons, Christine Vande Velde, Fany Panayi, Caroline Louis, Adriana Di Polo
BACKGROUND: Tau is an axon-enriched protein that binds to and stabilizes microtubules, and hence plays a crucial role in neuronal function. In Alzheimer's disease (AD), pathological tau accumulation correlates with cognitive decline. Substantial visual deficits are found in individuals affected by AD including a preferential loss of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. At present, however, the mechanisms that underlie vision changes in these patients are poorly understood...
August 3, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28768549/intranasal-insulin-reverts-central-pathology-and-cognitive-impairment-in-diabetic-mother-offspring
#17
Juan Jose Ramos-Rodriguez, Daniel Sanchez-Sotano, Alberto Doblas-Marquez, Carmen Infante-Garcia, Simon Lubian-Lopez, Monica Garcia-Alloza
BACKGROUND: Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Among these, chronic central complications in DMO remain poorly understood, and in extreme cases, diabetes can essentially function as a gestational brain insult. Nevertheless, therapeutic alternatives for DMO are limited. METHODS: Therefore, we have analyzed the central long-term complications in the offspring from CD1 diabetic mothers treated with streptozotozin, as well as the possible reversion of these alterations by insulin administration to neonates...
August 2, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28768545/trem2-in-neurodegenerative-diseases
#18
REVIEW
Taylor R Jay, Victoria E von Saucken, Gary E Landreth
TREM2 variants have been identified as risk factors for Alzheimer's disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer's disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics...
August 2, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28743268/the-lysosomal-protein-cathepsin-l-is-a-progranulin-protease
#19
Chris W Lee, Jeannette N Stankowski, Jeannie Chew, Casey N Cook, Ying-Wai Lam, Sandra Almeida, Yari Carlomagno, Kwok-Fai Lau, Mercedes Prudencio, Fen-Biao Gao, Matthew Bogyo, Dennis W Dickson, Leonard Petrucelli
Haploinsufficiency of GRN, the gene encoding progranulin (PGRN), causes frontotemporal lobar degeneration (FTLD), the second most common cause of early-onset dementia. Receptor-mediated lysosomal targeting has been shown to regulate brain PGRN levels, and complete deficiency of PGRN is a direct cause of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Here we show that the lysosomal cysteine protease cathepsin L (Cat L) can mediate the proteolytic cleavage of intracellular PGRN into poly-granulin and granulin fragments...
July 25, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28697798/a-proteomic-analysis-of-lrrk2-binding-partners-reveals-interactions-with-multiple-signaling-components-of-the-wnt-pcp-pathway
#20
Alena Salašová, Chika Yokota, David Potěšil, Zbyněk Zdráhal, Vítězslav Bryja, Ernest Arenas
BACKGROUND: Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients...
July 11, 2017: Molecular Neurodegeneration
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