754 results match your criteria Molecular Neurodegeneration [Journal]


Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease.

Mol Neurodegener 2019 04 12;14(1):15. Epub 2019 Apr 12.

Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: Based on epidemiological and experimental studies, type 2 diabetes mellitus (T2DM), especially insulin resistance that comprises the core mechanism of T2DM, has been recognized as a significant risk factor for Alzheimer's disease (AD). Studies in humans and diabetic AD model mice have indicated a correlation between insulin resistance and increased amyloid deposition in the brain. Paradoxically, mice with targeted disruption of genes involved in the insulin signaling pathway showed protective effects against the AD-related pathology. Read More

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http://dx.doi.org/10.1186/s13024-019-0315-7DOI Listing

Glial phagocytic clearance in Parkinson's disease.

Mol Neurodegener 2019 04 5;14(1):16. Epub 2019 Apr 5.

Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131, Padova, Italy.

An emerging picture suggests that glial cells' loss of beneficial roles or gain of toxic functions can contribute to neurodegenerative conditions. Among glial cells, microglia and astrocytes have been shown to play phagocytic roles by engulfing synapses, apoptotic cells, cell debris, and released toxic proteins. As pathogenic protein accumulation is a key feature in Parkinson's disease (PD), compromised phagocytic clearance might participate in PD pathogenesis. Read More

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http://dx.doi.org/10.1186/s13024-019-0314-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451240PMC

Functional networks are impaired by elevated tau-protein but reversible in a regulatable Alzheimer's disease mouse model.

Mol Neurodegener 2019 03 27;14(1):13. Epub 2019 Mar 27.

In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, D-50931, Cologne, Germany.

Background: Aggregation of tau proteins is a distinct hallmark of tauopathies and has been a focus of research and clinical trials for Alzheimer's Disease. Recent reports have pointed towards a toxic effect of soluble or oligomeric tau in the spreading of tau pathology in Alzheimer's disease. Here we investigated the effects of expressing human tau repeat domain (tauRD) with pro- or anti-aggregant mutations in regulatable transgenic mouse models of Alzheimer's Disease on the functional neuronal networks and the structural connectivity strength. Read More

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http://dx.doi.org/10.1186/s13024-019-0316-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438042PMC

Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis.

Mol Neurodegener 2019 03 27;14(1):14. Epub 2019 Mar 27.

Center for Integrative Biology, Faculty of Science, Universidad Mayor, Camino la Piramide 5750, P.O.BOX 70086, Santiago, Chile.

Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis. Read More

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http://dx.doi.org/10.1186/s13024-019-0313-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437924PMC
March 2019
1 Read

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice.

Mol Neurodegener 2019 03 5;14(1):12. Epub 2019 Mar 5.

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE, 68198-5880, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-019-0311-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399898PMC
March 2019
3 Reads
6.563 Impact Factor

Dural lymphatics regulate clearance of extracellular tau from the CNS.

Mol Neurodegener 2019 02 27;14(1):11. Epub 2019 Feb 27.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, 63110, USA.

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). Read More

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http://dx.doi.org/10.1186/s13024-019-0312-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391770PMC
February 2019
2 Reads

Sleep oscillation-specific associations with Alzheimer's disease CSF biomarkers: novel roles for sleep spindles and tau.

Mol Neurodegener 2019 02 21;14(1):10. Epub 2019 Feb 21.

Department of Psychiatry, NYU School of Medicine, New York, NY, 10016, USA.

Background: Based on associations between sleep spindles, cognition, and sleep-dependent memory processing, here we evaluated potential relationships between levels of CSF Aβ, 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 Aβ, P-tau and T-tau. Seven days of actigraphy were collected to assess habitual total sleep time. Read More

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http://dx.doi.org/10.1186/s13024-019-0309-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385427PMC
February 2019
2 Reads

Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy.

Mol Neurodegener 2019 02 15;14(1). Epub 2019 Feb 15.

Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA.

Background: A GC 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 GC and antisense GC 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 GC repeats were performed on postnatal day 0, followed by assessment of behavioral and neuropathological phenotypes. Read More

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http://dx.doi.org/10.1186/s13024-019-0310-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377782PMC
February 2019
1 Read

Differences in neurotropism and neurotoxicity among retrograde viral tracers.

Mol Neurodegener 2019 02 8;14(1). Epub 2019 Feb 8.

State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China.

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. Read More

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http://dx.doi.org/10.1186/s13024-019-0308-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368820PMC
February 2019
2 Reads

Reduced presynaptic vesicle stores mediate cellular and network plasticity defects in an early-stage mouse model of Alzheimer's disease.

Mol Neurodegener 2019 01 22;14(1). Epub 2019 Jan 22.

Department of Neuroscience, The Chicago Medical School; The Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL, 60064, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-019-0307-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343260PMC
January 2019
7 Reads

Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma.

Mol Neurodegener 2019 01 22;14(1). Epub 2019 Jan 22.

The Jackson Laboratory, Bar Harbor, ME, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0303-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341618PMC
January 2019
2 Reads

Dementia with Lewy bodies: an update and outlook.

Mol Neurodegener 2019 01 21;14(1). Epub 2019 Jan 21.

Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.

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. Read More

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http://dx.doi.org/10.1186/s13024-019-0306-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341685PMC
January 2019
2 Reads

Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses.

Mol Neurodegener 2019 01 16;14(1). Epub 2019 Jan 16.

Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland, 20892-1830, USA.

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. Read More

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https://molecularneurodegeneration.biomedcentral.com/article
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http://dx.doi.org/10.1186/s13024-018-0300-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335712PMC
January 2019
9 Reads

Glucose transporter 1 critically controls microglial activation through facilitating glycolysis.

Mol Neurodegener 2019 01 11;14(1). Epub 2019 Jan 11.

The Wellcome-Wolfson Institute of Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.

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. Read More

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https://molecularneurodegeneration.biomedcentral.com/article
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http://dx.doi.org/10.1186/s13024-019-0305-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329071PMC
January 2019
11 Reads

Recent advances and perspectives of metabolomics-based investigations in Parkinson's disease.

Mol Neurodegener 2019 01 11;14(1). Epub 2019 Jan 11.

Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, China.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0304-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330496PMC
January 2019
1 Read

Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology.

Mol Neurodegener 2019 01 10;14(1). Epub 2019 Jan 10.

Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0301-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327425PMC
January 2019
4 Reads

Proteolytic cleavage of Beclin 1 exacerbates neurodegeneration.

Mol Neurodegener 2018 12 29;13(1):68. Epub 2018 Dec 29.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0302-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310967PMC
December 2018
1 Read

Development and validation of a simplified method to generate human microglia from pluripotent stem cells.

Mol Neurodegener 2018 12 22;13(1):67. Epub 2018 Dec 22.

Department of Neurobiology & Behavior, University of California, 3014 Gross Hall, 845 Health Science Rd, Irvine, CA, 92697-4545, USA.

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). Read More

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http://dx.doi.org/10.1186/s13024-018-0297-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303871PMC
December 2018
1 Read

New insights into the role of TREM2 in Alzheimer's disease.

Mol Neurodegener 2018 12 20;13(1):66. Epub 2018 Dec 20.

Department of Neurology, St. Louis, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0298-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302500PMC
December 2018
2 Reads

Genome-wide RNAseq study of the molecular mechanisms underlying microglia activation in response to pathological tau perturbation in the rTg4510 tau transgenic animal model.

Mol Neurodegener 2018 12 17;13(1):65. Epub 2018 Dec 17.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.

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. Read More

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https://molecularneurodegeneration.biomedcentral.com/article
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http://dx.doi.org/10.1186/s13024-018-0296-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296031PMC
December 2018
15 Reads

Advances in developing novel therapeutic strategies for Alzheimer's disease.

Mol Neurodegener 2018 12 12;13(1):64. Epub 2018 Dec 12.

James J Peters VA Medical Center, Research & Development, Bronx, NY, 10468, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0299-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291983PMC
December 2018
1 Read

Disease-modifying effects of metabolic perturbations in ALS/FTLD.

Mol Neurodegener 2018 12 4;13(1):63. Epub 2018 Dec 4.

Department of Neurology, The McGovern Medical School of UT Health, Houston, TX, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0294-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278047PMC
December 2018
14 Reads

GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions.

Mol Neurodegener 2018 11 22;13(1):62. Epub 2018 Nov 22.

Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences Center, Shenzhen, 518060, Guangdong, China.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0295-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251088PMC
November 2018
14 Reads

Functional alterations of myeloid cells during the course of Alzheimer's disease.

Mol Neurodegener 2018 11 13;13(1):61. Epub 2018 Nov 13.

Department of Neurology, Houston Methodist Neurological Institute, 6560 Fannin St. Suite 802, Houston, TX, 77030, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0293-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233576PMC
November 2018
18 Reads

Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis.

Mol Neurodegener 2018 11 7;13(1):60. Epub 2018 Nov 7.

Neuroscience and Trauma Centre, Blizard Institute, Barts and The School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, City of London, Greater London, E1 2AT, UK.

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. Read More

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https://molecularneurodegeneration.biomedcentral.com/article
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http://dx.doi.org/10.1186/s13024-018-0292-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223075PMC
November 2018
12 Reads

A brain-penetrant triazolopyrimidine enhances microtubule-stability, reduces axonal dysfunction and decreases tau pathology in a mouse tauopathy model.

Mol Neurodegener 2018 11 7;13(1):59. Epub 2018 Nov 7.

Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St, Philadelphia, PA, 19104, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0291-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223064PMC
November 2018
18 Reads

Correction to: Peripheral immune system in aging and Alzheimer's disease.

Authors:
Wei Cao Hui Zheng

Mol Neurodegener 2018 10 24;13(1):58. Epub 2018 Oct 24.

Department of Molecular and Human Genetics, Baylor College of Medicine, Huffington Center on Aging, Houston, TX, 77030, USA.

The original article [1] contained several small omissions and errata contained in Tables 2 and 3; these errors have now been corrected. Read More

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http://dx.doi.org/10.1186/s13024-018-0290-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201538PMC
October 2018
1 Read

Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism.

Mol Neurodegener 2018 10 19;13(1):57. Epub 2018 Oct 19.

Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute and Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California, 90033, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0286-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194676PMC
October 2018
8 Reads

Essential roles of mitochondrial biogenesis regulator Nrf1 in retinal development and homeostasis.

Mol Neurodegener 2018 10 17;13(1):56. Epub 2018 Oct 17.

Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin St., MSB 7.024, Houston, TX, 77030, USA.

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. Read More

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https://molecularneurodegeneration.biomedcentral.com/article
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http://dx.doi.org/10.1186/s13024-018-0287-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192121PMC
October 2018
16 Reads

ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans.

Mol Neurodegener 2018 10 11;13(1):53. Epub 2018 Oct 11.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.

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). Read More

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http://dx.doi.org/10.1186/s13024-018-0289-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190665PMC
October 2018
7 Reads

Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice.

Mol Neurodegener 2018 10 16;13(1):55. Epub 2018 Oct 16.

Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven - University of Leuven, Leuven, Belgium.

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. Read More

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https://molecularneurodegeneration.biomedcentral.com/article
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http://dx.doi.org/10.1186/s13024-018-0288-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192075PMC
October 2018
15 Reads

Deregulation of neuronal miRNAs induced by amyloid-β or TAU pathology.

Mol Neurodegener 2018 10 12;13(1):54. Epub 2018 Oct 12.

VIB Center for Brain & Disease Research, Leuven, Belgium.

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 (APP/PS1) and TAUtg (THY-Tau22) mice and their wild-type littermates (APPwt and TAUwt). Read More

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https://molecularneurodegeneration.biomedcentral.com/article
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http://dx.doi.org/10.1186/s13024-018-0285-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186090PMC
October 2018
2 Reads

Deep proteomic network analysis of Alzheimer's disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease.

Mol Neurodegener 2018 10 4;13(1):52. Epub 2018 Oct 4.

Department of Neurology, Emory University School of Medicine, Whitehead Building-Suite 505C, 615 Michael Street, Atlanta, GA, 30322, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0282-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172707PMC
October 2018
11 Reads

Peripheral immune system in aging and Alzheimer's disease.

Authors:
Wei Cao Hui Zheng

Mol Neurodegener 2018 10 3;13(1):51. Epub 2018 Oct 3.

Department of Molecular and Human Genetics, Baylor College of Medicine, Huffington Center on Aging, Houston, TX, 77030, USA.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0284-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169078PMC
October 2018
1 Read

Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer's disease.

Mol Neurodegener 2018 09 26;13(1):50. Epub 2018 Sep 26.

reMYND NV, Gaston Geenslaan 1, Leuven-Heverlee, 3001, Belgium.

Background: Neuronal Ca 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 Ca influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential. Read More

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http://dx.doi.org/10.1186/s13024-018-0283-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158915PMC
September 2018
7 Reads

The Trem2 R47H Alzheimer's risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans.

Mol Neurodegener 2018 09 6;13(1):49. Epub 2018 Sep 6.

Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0280-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126019PMC
September 2018
4 Reads

Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice.

Mol Neurodegener 2018 09 4;13(1):48. Epub 2018 Sep 4.

Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0281-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123925PMC
September 2018
2 Reads

Alzheimer-associated cerebrospinal fluid fragments of neurogranin are generated by Calpain-1 and prolyl endopeptidase.

Mol Neurodegener 2018 08 29;13(1):47. Epub 2018 Aug 29.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0279-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116393PMC
August 2018
21 Reads

Subretinal macrophages produce classical complement activator C1q leading to the progression of focal retinal degeneration.

Mol Neurodegener 2018 08 20;13(1):45. Epub 2018 Aug 20.

The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0278-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102844PMC
August 2018
1 Read

Long-read sequencing across the C9orf72 'GGGGCC' repeat expansion: implications for clinical use and genetic discovery efforts in human disease.

Mol Neurodegener 2018 08 21;13(1):46. Epub 2018 Aug 21.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.

Background: Many neurodegenerative diseases are caused by nucleotide repeat expansions, but most expansions, like the C9orf72 'GGGGCC' (GC) 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 GC repeat expansion. Read More

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http://dx.doi.org/10.1186/s13024-018-0274-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102925PMC
August 2018
24 Reads

PU.1 regulates Alzheimer's disease-associated genes in primary human microglia.

Mol Neurodegener 2018 08 20;13(1):44. Epub 2018 Aug 20.

Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

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. Read More

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http://dx.doi.org/10.1186/s13024-018-0277-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102813PMC
August 2018
7 Reads

Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation.

Mol Neurodegener 2018 08 9;13(1):43. Epub 2018 Aug 9.

Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.

Background: Synucleinopathies of the aging population are an heterogeneous group of neurological disorders that includes Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and are characterized by the progressive accumulation of α-synuclein in neuronal and glial cells. Toll-like receptor 2 (TLR2), a pattern recognition immune receptor, has been implicated in the pathogenesis of synucleinopathies because TLR2 is elevated in the brains of patients with PD and TLR2 is a mediator of the neurotoxic and pro-inflammatory effects of extracellular α-synuclein aggregates. Therefore, blocking TLR2 might alleviate α-synuclein pathological and functional effects. Read More

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http://dx.doi.org/10.1186/s13024-018-0276-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085656PMC
August 2018
3 Reads

Counteracting roles of MHCI and CD8 T cells in the peripheral and central nervous system of ALS SOD1 mice.

Mol Neurodegener 2018 08 9;13(1):42. Epub 2018 Aug 9.

Laboratory of Molecular Neurobiology, Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.

Background: The major histocompatibility complex I (MHCI) is a key molecule for the interaction of mononucleated cells with CD8T lymphocytes. We previously showed that MHCI is upregulated in the spinal cord microglia and motor axons of transgenic SOD1 mice.

Methods: To assess the role of MHCI in the disease, we examined transgenic SOD1 mice crossbred with β2 microglobulin-deficient mice, which express little if any MHCI on the cell surface and are defective for CD8 T cells. Read More

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http://dx.doi.org/10.1186/s13024-018-0271-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085701PMC
August 2018
6 Reads

Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases.

Mol Neurodegener 2018 08 8;13(1):41. Epub 2018 Aug 8.

Interdepartmental Program in Bioinformatics, University of California, Los Angeles, CA, 90095, USA.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.

Methods: We conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry.

Results: We identified 5 associated loci at a genome-wide significance threshold P < 5 × 10, including replication of 3 loci from previous studies and 2 novel loci at 6p21. Read More

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http://dx.doi.org/10.1186/s13024-018-0270-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083608PMC
August 2018
23 Reads

A new hypothesis for Parkinson's disease pathogenesis: GTPase-p38 MAPK signaling and autophagy as convergence points of etiology and genomics.

Mol Neurodegener 2018 08 2;13(1):40. Epub 2018 Aug 2.

Institute for Biomedicine, Eurac Research - Affiliated Institute of the University of Lübeck, Via Galvani 31, 39100, Bolzano, Italy.

The combination of genetics and genomics in Parkinson´s disease has recently begun to unveil molecular mechanisms possibly underlying disease onset and progression. In particular, catabolic processes such as autophagy have been increasingly gaining relevance as post-mortem evidence and experimental models suggested a participation in neurodegeneration and alpha-synuclein Lewy body pathology. In addition, familial Parkinson´s disease linked to LRRK2 and alpha-synuclein provided stronger correlation between etiology and alterations in autophagy. Read More

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http://dx.doi.org/10.1186/s13024-018-0273-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090926PMC
August 2018
4 Reads

Transcriptional profiling of HERV-K(HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins.

Mol Neurodegener 2018 08 2;13(1):39. Epub 2018 Aug 2.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. About 90% of ALS cases are without a known genetic cause. The human endogenous retrovirus multi-copy HERV-K(HML-2) group was recently reported to potentially contribute to neurodegeneration and disease pathogenesis in ALS because of transcriptional upregulation and toxic effects of HML-2 Envelope (Env) protein. Read More

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http://dx.doi.org/10.1186/s13024-018-0275-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091006PMC
August 2018
5 Reads

Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain.

Mol Neurodegener 2018 07 24;13(1):38. Epub 2018 Jul 24.

Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 630 West 168th Street, PH 19 - 302, New York, NY, 10032, USA.

Background: The role of the innate immune system in Alzheimer's disease (AD) and neurodegenerative disease susceptibility has recently been highlighted in genetic studies. However, we do not know whether risk for inflammatory disease predisposes unaffected individuals to late-life cognitive deficits or AD-related neuropathology. We investigated whether genetic risk scores for seven immune diseases and central nervous system traits were related to cognitive decline (n = 1601), classical AD neuropathology (n = 985), or microglial density (n = 184). Read More

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http://dx.doi.org/10.1186/s13024-018-0272-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057096PMC
July 2018
9 Reads

Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci.

Mol Neurodegener 2018 07 9;13(1):37. Epub 2018 Jul 9.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Background: Progressive supranuclear palsy (PSP) is a parkinsonian neurodegenerative tauopathy affecting brain regions involved in motor function, including the basal ganglia, diencephalon and brainstem. While PSP is largely considered to be a sporadic disorder, cases with suspected familial inheritance have been identified and the common MAPT H1haplotype is a major genetic risk factor. Due to the relatively low prevalence of PSP, large sample sizes can be difficult to achieve, and this has limited the ability to detect true genetic risk factors at the genome-wide statistical threshold for significance in GWAS data. Read More

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http://dx.doi.org/10.1186/s13024-018-0267-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038352PMC
July 2018
6 Reads

Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China.

Mol Neurodegener 2018 07 6;13(1):36. Epub 2018 Jul 6.

Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.

Background: Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. Read More

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http://dx.doi.org/10.1186/s13024-018-0269-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035405PMC
July 2018
16 Reads

TMEM106B haplotypes have distinct gene expression patterns in aged brain.

Mol Neurodegener 2018 07 3;13(1):35. Epub 2018 Jul 3.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Background: Single nucleotide polymorphisms (SNPs) inherited as one of two common haplotypes at the transmembrane protein 106B (TMEM106B) locus are associated with the risk of multiple neurodegenerative diseases, including frontotemporal lobar degeneration with pathological inclusions of TDP-43. Among the associated variants, rs3173615 (encoding p.T185S) is the only coding variant; however, non-coding variants may also contribute to disease risk. Read More

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http://dx.doi.org/10.1186/s13024-018-0268-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029036PMC
July 2018
9 Reads