719 results match your criteria tdp-43 identified

Network Analysis of the CSF Proteome Characterizes Convergent Pathways of Cellular Dysfunction in ALS.

Front Neurosci 2021 17;15:642324. Epub 2021 Mar 17.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Background: Amyotrophic lateral sclerosis is a clinical syndrome with complex biological determinants, but which in most cases is characterized by TDP-43 pathology. The identification in CSF of a protein signature of TDP-43 network dysfunction would have the potential to inform the identification of new biomarkers and therapeutic targets.

Methods: We compared CSF proteomic data from patients with ALS ( = 41), Parkinson's disease ( = 19) and healthy control participants ( = 20). Read More

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The Delayed Neuropathological Consequences of Traumatic Brain Injury in a Community-Based Sample.

Front Neurol 2021 16;12:624696. Epub 2021 Mar 16.

Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, United States.

The late neuropathological effects of traumatic brain injury have yet to be fully elucidated, particularly with respect to community-based cohorts. To contribute to this critical gap in knowledge, we designed a multimodal neuropathological study, integrating traditional and quantitative approaches to detect pathologic changes in 532 consecutive brain autopsies from participants in the Adult Changes in Thought (ACT) study. Diagnostic evaluation including assessment for chronic traumatic encephalopathy (CTE) and quantitative immunoassay-based methods were deployed to examine levels of pathological (hyperphosphorylated) tau (pTau) and amyloid (A) β in brains from ACT participants with ( = 107) and without ( = 425) history of remote TBI with loss of consciousness (w/LOC). Read More

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TDP-43 maintains chondrocyte homeostasis and alleviates cartilage degradation in osteoarthritis.

Osteoarthritis Cartilage 2021 Mar 26. Epub 2021 Mar 26.

State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China. Electronic address:

Objective: Osteoarthritis (OA) is the most prevalent age-related disorder due to cartilage degradation. Previous studies have identified aberrant chondrocyte homeostasis under extracellular stress as a key pathological mechanism behind cartilage degradation in OA. TDP-43, a DNA/RNA-binding protein has been demonstrated to participate in processing many extracellular stress responses; however, understanding of the role of TDP-43 in OA is limited. Read More

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TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6.

Acta Neuropathol Commun 2021 03 24;9(1):52. Epub 2021 Mar 24.

Department of Cellular and Molecular Biology, University of Arizona, 1007 E. Lowell St, LSS RM 548A, Tucson, AZ, 85721, USA.

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Read More

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Loss of the metabolism and sleep regulating neuronal populations expressing orexin and oxytocin in the hypothalamus in amyotrophic lateral sclerosis.

Neuropathol Appl Neurobiol 2021 Mar 23. Epub 2021 Mar 23.

Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.

Aims: To determine the underlying cellular changes and clinical correlates associated with pathology of the hypothalamus in amyotrophic lateral sclerosis (ALS), as hypothalamic atrophy occurs in the preclinical phase of the disease.

Methods: The hypothalamus was pathologically examined in nine patients with amyotrophic lateral sclerosis in comparison to eight healthy control subjects. The severity of regional atrophy (paraventricular nucleus: PVN, fornix and total hypothalamus) and peptidergic neuronal loss (oxytocin, vasopressin, cocaine- and amphetamine-regulating transcript: CART, and orexin) was correlated with changes in eating behaviour, sleep function, cognition, behaviour and disease progression. Read More

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ALS/FTD-causing mutation in cyclin F causes the dysregulation of SFPQ.

Hum Mol Genet 2021 Mar 17. Epub 2021 Mar 17.

Department of Biomedical Sciences, Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, 2 Technology Place, North Ryde, NSW 2109, Australia.

Previously, we identified missense mutations in CCNF that are causative of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Hallmark features of these diseases include the build-up of insoluble protein aggregates as well as the mislocalisation of proteins such as TDP-43. In recent years, the dysregulation of SFPQ has also emerged as a pathological hallmark of ALS/FTD. Read More

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Multiple ways to a dead end: diverse mechanisms by which ALS mutant genes induce cell death.

Cell Cycle 2021 Mar 15:1-16. Epub 2021 Mar 15.

Department of Biological Sciences, Columbia University, New York, NY, United States.

Amyotrophic Lateral Sclerosis (ALS) is a deadly neuromuscular disorder caused by progressive motor neuron loss in the brain and spinal cord. Over the past decades, a number of genetic mutations have been identified that cause or are associated with ALS disease progression. Numerous genes harbor ALS mutations, and they encode proteins displaying a wide range of physiological functions, with limited overlap. Read More

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Hippocampal Sclerosis in Frontotemporal Dementia: When Vascular Pathology Meets Neurodegeneration.

J Neuropathol Exp Neurol 2021 Mar;80(4):313-324

Institute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of Antwerp, Antwerp, Belgium.

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified. Read More

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Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology.

Clin Transl Med 2021 Feb;11(2):e336

Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Background: Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. Read More

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February 2021

Nucleolar stress in C9orf72 and sporadic ALS spinal motor neurons precedes TDP-43 mislocalization.

Acta Neuropathol Commun 2021 02 15;9(1):26. Epub 2021 Feb 15.

University of California, San Diego, La Jolla, CA, USA.

Nucleolar stress has been implicated in the pathology and disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) from repeat expansions of GGGGCC in C9orf72 (C9-ALS/FTLD) but not in sporadic ALS (SALS). Previously we reported that antisense RNA transcripts are unique in C9-ALS because of their nucleolar localization in spinal motor neurons and correlation with TDP-43 mislocalization, the hallmark proteinopathy of ALS and FTLD. Here we report our further studies of 11 SALS, 11 C9-ALS and 11 control spinal cords. Read More

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February 2021

Genetics of frontotemporal dementia in China.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Feb 4:1-15. Epub 2021 Feb 4.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

: Frontotemporal dementia (FTD) is the second most common presenile dementia, characterized by prominent behavioral, language, and cognitive impairment, which has a strong genetic component contributing to its pathogenesis. Due to geographical and ethnic variability, the prevalence of the causative genes of FTD may be different. : To explore the genetics of FTD in the Chinese population, we reviewed 97 closely related studies that were searched in PubMed and Web of Science. Read More

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February 2021

TDP-43 Regulation of AChE Expression Can Mediate ALS-Like Phenotype in Zebrafish.

Cells 2021 Jan 22;10(2). Epub 2021 Jan 22.

Team "Translational Research for Neuronlogical Diseases", Institut Imagine Inserm U1163, Université de Paris; Sorbonne Université, Université Pierre et Marie Curie (UPMC), Université de Paris 06, Unité Mixte 75, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1127, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 7225 Institut du Cerveau et de la Moelle Épinière (ICM), 75013 Paris, France.

The "distal axonopathy" hypothesis in amyotrophic lateral sclerosis (ALS) proposes that pathological changes occur at the neuromuscular junction (NMJ) early in the disease. While acetylcholinesterase (AChE) plays an important role in the functionality of the NMJ, its potential role in ALS remains unexplored. Here, we identified AChE as a limiting factor regulating muscle/motor neuron connection in a vertebrate model of ALS. Read More

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January 2021

Amyotrophic Lateral Sclerosis Genes in .

Int J Mol Sci 2021 Jan 18;22(2). Epub 2021 Jan 18.

The Neuroscience Institute of Montpellier, INSERM, University of Montpellier, 34091 Montpellier, France.

Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by the progressive degeneration of upper and lower motoneurons. Most ALS cases are sporadic but approximately 10% of ALS cases are due to inherited mutations in identified genes. ALS-causing mutations were identified in over 30 genes with (), (), and (, encoding TDP-43) being the most frequent. Read More

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January 2021

Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease.

Parkinsonism Relat Disord 2021 Feb 12;83:49-53. Epub 2021 Jan 12.

Department of Neurology, Fukuoka University, Fukuoka, 8140180, Japan. Electronic address:

Introduction: Perry disease (Perry syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. Read More

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February 2021

Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice.

Acta Neuropathol Commun 2021 01 18;9(1):15. Epub 2021 Jan 18.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.

Transactive response DNA-binding protein 43 kDa (TDP-43) has been identified as the major component of ubiquitinated inclusions found in patients with sporadic amyotrophic lateral sclerosis (ALS). Increasing evidence suggests prion-like transmission of TDP-43 aggregates via neuroanatomic connection in vitro and pyramidal tract in vivo. However, it is still unknown whether the spreading of pathological TDP-43 sequentially via pyramidal tract can initiate ALS-like pathology and phenotypes. Read More

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January 2021

Pathobiological Subtypes of Alzheimer Disease.

Kurt A Jellinger

Dement Geriatr Cogn Disord 2020 11;49(4):321-333. Epub 2021 Jan 11.

Institute of Clinical Neurobiology, Vienna, Austria,

Alzheimer disease (AD), the most common form of dementia, is a heterogenous disorder with various pathobiological subtypes. In addition to the 4 major subtypes based on the distribution of tau pathology and brain atrophy (typical, limbic predominant, hippocampal sparing, and minimal atrophy [MA]), several other clinical variants showing distinct regional patterns of tau burden have been identified: nonamnestic, corticobasal syndromal, primary progressive aphasia, posterior cortical atrophy, behavioral/dysexecutive, and mild dementia variants. Among the subtypes, differences were found in age at onset, sex distribution, cognitive status, disease duration, APOE genotype, and biomarker levels. Read More

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January 2021

TDP-43 Vasculopathy in the Spinal Cord in Sporadic Amyotrophic Lateral Sclerosis (sALS) and Frontal Cortex in sALS/FTLD-TDP.

J Neuropathol Exp Neurol 2021 Feb;80(3):229-239

Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain.

Sporadic amyotrophic lateral sclerosis (sALS) and FTLD-TDP are neurodegenerative diseases within the spectrum of TDP-43 proteinopathies. Since abnormal blood vessels and altered blood-brain barrier have been described in sALS, we wanted to know whether TDP-43 pathology also occurs in blood vessels in sALS/FTLD-TDP. TDP-43 deposits were identified in association with small blood vessels of the spinal cord in 7 of 14 cases of sALS and in small blood vessels of frontal cortex area 8 in 6 of 11 FTLD-TDP and sALS cases, one of them carrying a GRN mutation. Read More

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February 2021

RNA packaging into extracellular vesicles: An orchestra of RNA-binding proteins?

J Extracell Vesicles 2020 Dec 28;10(2):e12043. Epub 2020 Dec 28.

Department of Cellular Computational and Integrative Biology (CIBIO) University of Trento Trento Italy.

Extracellular vesicles (EVs) are heterogeneous membranous particles released from the cells through different biogenetic and secretory mechanisms. We now conceive EVs as shuttles mediating cellular communication, carrying a variety of molecules resulting from intracellular homeostatic mechanisms. The RNA is a widely detected cargo and, impressively, a recognized functional intermediate that elects EVs as modulators of cancer cell phenotypes, determinants of disease spreading, cell surrogates in regenerative medicine, and a source for non-invasive molecular diagnostics. Read More

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December 2020

Skeletal Muscle-Restricted Expression of Human SOD1 in Transgenic Mice Causes a Fatal ALS-Like Syndrome.

Front Neurol 2020 14;11:592851. Epub 2020 Dec 14.

Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disease that causes motor neuron (MN) loss and skeletal muscle paralysis. It is uncertain whether this degeneration of MNs is triggered intrinsically and is autonomous, or if the disease initiating mechanisms are extrinsic to MNs. We hypothesized that skeletal muscle is a primary site of pathogenesis in ALS that triggers MN degeneration. Read More

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December 2020

Nuclear Import Receptors Directly Bind to Arginine-Rich Dipeptide Repeat Proteins and Suppress Their Pathological Interactions.

Cell Rep 2020 Dec;33(12):108538

BioMedical Center (BMC), Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany; LMU Graduate School of Systemic Neurosciences (GSN), 82152 Planegg-Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany. Electronic address:

Nuclear import receptors, also called importins, mediate nuclear import of proteins and chaperone aggregation-prone cargoes (e.g., neurodegeneration-linked RNA-binding proteins [RBPs]) in the cytoplasm. Read More

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December 2020

HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells.

Science 2021 02 17;371(6529). Epub 2020 Dec 17.

Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.

The RNA binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. In this study, we found that RNA binding-deficient TDP-43 (produced by neurodegeneration-causing mutations or posttranslational acetylation in its RNA recognition motifs) drove TDP-43 demixing into intranuclear liquid spherical shells with liquid cores. These droplets, which we named "anisosomes", have shells that exhibit birefringence, thus indicating liquid crystal formation. Read More

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February 2021

Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3.

Elife 2020 12 11;9. Epub 2020 Dec 11.

Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea.

Cytoplasmic accumulation of TDP-43 in motor neurons is the most prominent pathological feature in amyotrophic lateral sclerosis (ALS). A feedback cycle between nucleocytoplasmic transport (NCT) defect and TDP-43 aggregation was shown to contribute to accumulation of TDP-43 in the cytoplasm. However, little is known about cellular factors that can control the activity of NCT, thereby affecting TDP-43 accumulation in the cytoplasm. Read More

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December 2020

Stress Granule Dysregulation in Amyotrophic Lateral Sclerosis.

Front Cell Neurosci 2020 17;14:598517. Epub 2020 Nov 17.

Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with no current cure. ALS causes degeneration of both upper and lower motor neurons leading to atrophy of the innervating muscles and progressive paralysis. The exact mechanism of the pathology of ALS is unknown. Read More

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November 2020

Adult onset pan-neuronal human tau tubulin kinase 1 expression causes severe cerebellar neurodegeneration in mice.

Acta Neuropathol Commun 2020 11 23;8(1):200. Epub 2020 Nov 23.

Geriatrics Research Education and Clinical Center, Seattle Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA, 98108, USA.

The kinase TTBK1 is predominantly expressed in the central nervous system and has been implicated in neurodegenerative diseases including Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis through its ability to phosphorylate the proteins tau and TDP-43. Mutations in the closely related gene TTBK2 cause spinocerebellar ataxia, type 11. However, it remains unknown whether altered TTBK1 activity alone can drive neurodegeneration. Read More

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November 2020

Stress-Specific Spatiotemporal Responses of RNA-Binding Proteins in Human Stem-Cell-Derived Motor Neurons.

Int J Mol Sci 2020 Nov 6;21(21). Epub 2020 Nov 6.

Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.

RNA-binding proteins (RBPs) have been shown to play a key role in the pathogenesis of a variety of neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is an exemplar neurodegenerative disease characterised by rapid progression and relatively selective motor neuron loss. Nuclear-to-cytoplasmic mislocalisation and accumulation of RBPs have been identified as a pathological hallmark of the disease, yet the spatiotemporal responses of RBPs to different extrinsic stressors in human neurons remain incompletely understood. Read More

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November 2020

Somatic TARDBP variants as a cause of semantic dementia.

Brain 2020 12;143(12):3827-3841

Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.

The aetiology of late-onset neurodegenerative diseases is largely unknown. Here we investigated whether de novo somatic variants for semantic dementia can be detected, thereby arguing for a more general role of somatic variants in neurodegenerative disease. Semantic dementia is characterized by a non-familial occurrence, early onset (<65 years), focal temporal atrophy and TDP-43 pathology. Read More

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December 2020

Nonmuscle myosin IIB regulates Parkin-mediated mitophagy associated with amyotrophic lateral sclerosis-linked TDP-43.

Cell Death Dis 2020 11 5;11(11):952. Epub 2020 Nov 5.

Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, 34054, Republic of Korea.

C-terminal fragments of Tar DNA-binding protein 43 (TDP-43) have been identified as the major pathological protein in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how they affect cellular toxicity and neurodegeneration, including the modulation process remains unknown. This study revealed that the C-terminal fragment of TDP-43 (TDP-25) was localized primarily to mitochondria and caused abnormal mitochondrial morphology, inducing Parkin-mediated mitophagy. Read More

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November 2020

Frontotemporal dementia-linked P112H mutation of TDP-43 induces protein structural change and impairs its RNA binding function.

Protein Sci 2021 Feb 23;30(2):350-365. Epub 2020 Nov 23.

Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.

TDP-43 forms the primary constituents of the cytoplasmic inclusions contributing to various neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). Over 60 TDP-43 mutations have been identified in patients suffering from these two diseases, but most variations are located in the protein's disordered C-terminal glycine-rich region. P112H mutation of TDP-43 has been uniquely linked to FTD, and is located in the first RNA recognition motif (RRM1). Read More

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February 2021

Protein contributions to brain atrophy acceleration in Alzheimer's disease and primary age-related tauopathy.

Brain 2020 12;143(11):3463-3476

Department of Radiology (Radiology Research) Mayo Clinic, Rochester, MN, USA.

Alzheimer's disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. Read More

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December 2020

APOE2: protective mechanism and therapeutic implications for Alzheimer's disease.

Mol Neurodegener 2020 11 4;15(1):63. Epub 2020 Nov 4.

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

Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer's disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Read More

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November 2020