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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
Irene Zubiri, Vittoria Lombardi, Michael Bremang, Vikram Mitra, Giovanni Nardo, Rocco Adiutori, Ching-Hua Lu, Emanuela Leoni, Ping Yip, Ozlem Yildiz, Malcolm Ward, Linda Greensmith, Caterina Bendotti, Ian Pike, Andrea Malaspina
BACKGROUND: It is unclear to what extent pre-clinical studies in genetically homogeneous animal models of amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disorder, can be informative of human pathology. The disease modifying effects in animal models of most therapeutic compounds have not been reproduced in patients. To advance therapeutics in ALS, we need easily accessible disease biomarkers which can discriminate across the phenotypic variants observed in ALS patients and can bridge animal and human pathology...
November 7, 2018: Molecular Neurodegeneration
Bin Zhang, Yuemang Yao, Anne-Sophie Cornec, Killian Oukoloff, Michael J James, Pyry Koivula, John Q Trojanowski, Amos B Smith, Virginia M-Y Lee, Carlo Ballatore, Kurt R Brunden
BACKGROUND: Alzheimer's disease (AD) and related tauopathies are neurodegenerative diseases that are characterized by the presence of insoluble inclusions of the protein tau within brain neurons and often glia. Tau is normally found associated with axonal microtubules (MTs) in the brain, and in tauopathies this MT binding is diminished due to tau hyperphosphorylation. As MTs play a critical role in the movement of cellular constituents within neurons via axonal transport, it is likely that the dissociation of tau from MTs alters MT structure and axonal transport, and there is evidence of this in tauopathy mouse models as well as in AD brain...
November 7, 2018: Molecular Neurodegeneration
Wei Cao, Hui Zheng
The original article [1] contained several small omissions and errata contained in Tables 2 and 3; these errors have now been corrected.
October 24, 2018: Molecular Neurodegeneration
Qingyi Ma, Zhen Zhao, Abhay P Sagare, Yingxi Wu, Min Wang, Nelly Chuqui Owens, Philip B Verghese, Joachim Herz, David M Holtzman, Berislav V Zlokovic
BACKGROUND: Clearance at the blood-brain barrier (BBB) plays an important role in removal of Alzheimer's amyloid-β (Aβ) toxin from brain both in humans and animal models. Apolipoprotein E (apoE), the major genetic risk factor for AD, disrupts Aβ clearance at the BBB. The cellular and molecular mechanisms, however, still remain unclear, particularly whether the BBB-associated brain capillary pericytes can contribute to removal of aggregated Aβ from brain capillaries, and whether removal of Aβ aggregates by pericytes requires apoE, and if so, is Aβ clearance on pericytes apoE isoform-specific...
October 19, 2018: Molecular Neurodegeneration
Takae Kiyama, Ching-Kang Chen, Steven W Wang, Ping Pan, Zhenlin Ju, Jing Wang, Shinako Takada, William H Klein, Chai-An Mao
BACKGROUND: Mitochondrial dysfunction has been implicated in the pathologies of a number of retinal degenerative diseases in both the outer and inner retina. In the outer retina, photoreceptors are particularly vulnerable to mutations affecting mitochondrial function due to their high energy demand and sensitivity to oxidative stress. However, it is unclear how defective mitochondrial biogenesis affects neural development and contributes to neural degeneration. In this report, we investigated the in vivo function of nuclear respiratory factor 1 (Nrf1), a major transcriptional regulator of mitochondrial biogenesis in both proliferating retinal progenitor cells (RPCs) and postmitotic rod photoreceptor cells (PRs)...
October 17, 2018: Molecular Neurodegeneration
Sander Beel, Sarah Herdewyn, Raheem Fazal, Mathias De Decker, Matthieu Moisse, Wim Robberecht, Ludo Van Den Bosch, Philip Van Damme
BACKGROUND: TAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). TDP-43 pathology is not restricted to patients with missense mutations in TARDBP, the gene encoding TDP-43, but also occurs in ALS/FTD patients without known genetic cause or in patients with various other ALS/FTD gene mutations. Mutations in progranulin (GRN), which result in a reduction of ~ 50% of progranulin protein (PGRN) levels, cause FTD with TDP-43 pathology...
October 16, 2018: Molecular Neurodegeneration
Annerieke Sierksma, Ashley Lu, Evgenia Salta, Elke Vanden Eynden, Zsuzsanna Callaerts-Vegh, Rudi D'Hooge, David Blum, Luc Buée, Mark Fiers, Bart De Strooper
BACKGROUND: Despite diverging levels of amyloid-β (Aβ) and TAU pathology, different mouse models, as well as sporadic AD patients show predictable patterns of episodic memory loss. MicroRNA (miRNA) deregulation is well established in AD brain but it is unclear whether Aβ or TAU pathology drives those alterations and whether miRNA changes contribute to cognitive decline. METHODS: miRNAseq was performed on cognitively intact (4 months) and impaired (10 months) male APPtg (APPswe /PS1L166P ) and TAUtg (THY-Tau22) mice and their wild-type littermates (APPwt and TAUwt)...
October 12, 2018: Molecular Neurodegeneration
Olivia J Conway, Minerva M Carrasquillo, Xue Wang, Jenny M Bredenberg, Joseph S Reddy, Samantha L Strickland, Curtis S Younkin, Jeremy D Burgess, Mariet Allen, Sarah J Lincoln, Thuy Nguyen, Kimberly G Malphrus, Alexandra I Soto, Ronald L Walton, Bradley F Boeve, Ronald C Petersen, John A Lucas, Tanis J Ferman, William P Cheshire, Jay A van Gerpen, Ryan J Uitti, Zbigniew K Wszolek, Owen A Ross, Dennis W Dickson, Neill R Graff-Radford, Nilüfer Ertekin-Taner
BACKGROUND: Rare coding variants ABI3_rs616338-T and PLCG2_rs72824905-G were identified as risk or protective factors, respectively, for Alzheimer's disease (AD). METHODS: We tested the association of these variants with five neurodegenerative diseases in Caucasian case-control cohorts: 2742 AD, 231 progressive supranuclear palsy (PSP), 838 Parkinson's disease (PD), 306 dementia with Lewy bodies (DLB) and 150 multiple system atrophy (MSA) vs. 3351 controls; and in an African-American AD case-control cohort (181 AD, 331 controls)...
October 11, 2018: Molecular Neurodegeneration
Erik C B Johnson, Eric B Dammer, Duc M Duong, Luming Yin, Madhav Thambisetty, Juan C Troncoso, James J Lah, Allan I Levey, Nicholas T Seyfried
BACKGROUND: The complicated cellular and biochemical changes that occur in brain during Alzheimer's disease are poorly understood. In a previous study we used an unbiased label-free quantitative mass spectrometry-based proteomic approach to analyze these changes at a systems level in post-mortem cortical tissue from patients with Alzheimer's disease (AD), asymptomatic Alzheimer's disease (AsymAD), and controls. We found modules of co-expressed proteins that correlated with AD phenotypes, some of which were enriched in proteins identified as risk factors for AD by genetic studies...
October 4, 2018: Molecular Neurodegeneration
Wei Cao, Hui Zheng
Alzheimer's disease (AD) represents an urgent public health mandate. AD is no longer considered a neural-centric disease; rather, a plethora of recent studies strongly implicate a critical role played by neuroinflammation in the pathogeneses of AD and other neurodegenerative conditions. A close functional connection between the immune system and central nervous system is increasingly recognized. In late-onset AD, aging represents the most significant risk factor. Here, from an immunological perspective, we summarize the prominent molecular and cellular changes in the periphery of aging individuals and AD patients...
October 3, 2018: Molecular Neurodegeneration
Michael Dumbacher, Tom Van Dooren, Katrien Princen, Koen De Witte, Mélissa Farinelli, Sam Lievens, Jan Tavernier, Wim Dehaen, Stefaan Wera, Joris Winderickx, Sara Allasia, Amuri Kilonda, Stéphane Spieser, Arnaud Marchand, Patrick Chaltin, Casper C Hoogenraad, Gerard Griffioen
BACKGROUND: Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer's disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer's disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential...
September 26, 2018: Molecular Neurodegeneration
Xianyuan Xiang, Thomas M Piers, Benedikt Wefers, Kaichuan Zhu, Anna Mallach, Bettina Brunner, Gernot Kleinberger, Wilbur Song, Marco Colonna, Jochen Herms, Wolfgang Wurst, Jennifer M Pocock, Christian Haass
BACKGROUND: The R47H variant of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) significantly increases the risk for late onset Alzheimer's disease. Mouse models accurately reproducing phenotypes observed in Alzheimer' disease patients carrying the R47H coding variant are required to understand the TREM2 related dysfunctions responsible for the enhanced risk for late onset Alzheimer's disease. METHODS: A CRISPR/Cas9-assisted gene targeting strategy was used to generate Trem2 R47H knock-in mice...
September 6, 2018: Molecular Neurodegeneration
Julia K Götzl, Alessio-Vittorio Colombo, Katrin Fellerer, Anika Reifschneider, Georg Werner, Sabina Tahirovic, Christian Haass, Anja Capell
BACKGROUND: Heterozygous loss-of-function mutations in the progranulin gene (GRN) lead to frontotemporal lobar degeneration (FTLD) while the complete loss of progranulin (PGRN) function results in neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Thus the growth factor-like protein PGRN may play an important role in lysosomal degradation. In line with a potential lysosomal function, PGRN is partially localized and processed in lysosomes. In the central nervous system (CNS), PGRN is like other lysosomal proteins highly expressed in microglia, further supporting an important role in protein degradation...
September 4, 2018: Molecular Neurodegeneration
Bruno Becker, Faisal Hayat Nazir, Gunnar Brinkmalm, Elena Camporesi, Hlin Kvartsberg, Erik Portelius, Martina Boström, Marie Kalm, Kina Höglund, Maria Olsson, Henrik Zetterberg, Kaj Blennow
BACKGROUND: Neurogranin (Ng) is a small 7.6 kDa postsynaptic protein that has been detected at elevated concentrations in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), both as a full-length molecule and as fragments from its C-terminal half. Ng is involved in postsynaptic calcium (Ca) signal transduction and memory formation via binding to calmodulin in a Ca-dependent manner. The mechanism of Ng secretion from neurons to CSF is currently unknown, but enzymatic cleavage of Ng may be of relevance...
August 29, 2018: Molecular Neurodegeneration
Mark T W Ebbert, Stefan L Farrugia, Jonathon P Sens, Karen Jansen-West, Tania F Gendron, Mercedes Prudencio, Ian J McLaughlin, Brett Bowman, Matthew Seetin, Mariely DeJesus-Hernandez, Jazmyne Jackson, Patricia H Brown, Dennis W Dickson, Marka van Blitterswijk, Rosa Rademakers, Leonard Petrucelli, John D Fryer
BACKGROUND: Many neurodegenerative diseases are caused by nucleotide repeat expansions, but most expansions, like the C9orf72 'GGGGCC' (G4 C2 ) repeat that causes approximately 5-7% of all amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases, are too long to sequence using short-read sequencing technologies. It is unclear whether long-read sequencing technologies can traverse these long, challenging repeat expansions. Here, we demonstrate that two long-read sequencing technologies, Pacific Biosciences' (PacBio) and Oxford Nanopore Technologies' (ONT), can sequence through disease-causing repeats cloned into plasmids, including the FTD/ALS-causing G4 C2 repeat expansion...
August 21, 2018: Molecular Neurodegeneration
Haihan Jiao, Matt Rutar, Nilisha Fernando, Ted Yednock, Sethu Sankaranarayanan, Riemke Aggio-Bruce, Jan Provis, Riccardo Natoli
BACKGROUND: The role of the alternative complement pathway and its mediation by retinal microglia and macrophages, is well-established in the pathogenesis of Age-Related Macular Degeneration (AMD). However, the contribution of the classical complement pathway towards the progression of retinal degenerations is not fully understood, including the role of complement component 1q (C1q) as a critical activator molecule of the classical pathway. Here, we investigated the contribution of C1q to progressive photoreceptor loss and neuroinflammation in retinal degenerations...
August 20, 2018: Molecular Neurodegeneration
Justin Rustenhoven, Amy M Smith, Leon C Smyth, Deidre Jansson, Emma L Scotter, Molly E V Swanson, Miranda Aalderink, Natacha Coppieters, Pritika Narayan, Renee Handley, Chris Overall, Thomas I H Park, Patrick Schweder, Peter Heppner, Maurice A Curtis, Richard L M Faull, Mike Dragunow
BACKGROUND: Microglia play critical roles in the brain during homeostasis and pathological conditions. Understanding the molecular events underpinning microglial functions and activation states will further enable us to target these cells for the treatment of neurological disorders. The transcription factor PU.1 is critical in the development of myeloid cells and a major regulator of microglial gene expression. In the brain, PU.1 is specifically expressed in microglia and recent evidence from genome-wide association studies suggests that reductions in PU...
August 20, 2018: Molecular Neurodegeneration
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