Trafficking and Proteolytic Processing of APP

Cold Spring Harbor Perspectives in Medicine, Journal Year: 2012, Volume and Issue: 2(5), P. a006270 - a006270

Published: Feb. 7, 2012

Christian Haass1, Christoph Kaether2, Gopal Thinakaran3 and Sangram Sisodia3 DZNE—German Center for Neurodegenerative Diseases, 80336 Munich, Germany; Adolf Butenandt-Institute, Biochemistry, Ludwig-Maximilians University, Germany Leibniz Institut für Altersforschung, D-07745 Jena, Department of Neurobiology, University Chicago, Illinois 60637 Correspondence: christian.haass{at}dzne.lmu.de; ssisodia{at}bsd.uchicago.edu

Language: Английский

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TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia

Neuron, Journal Year: 2016, Volume and Issue: 91(2), P. 328 - 340

Published: July 1, 2016

Language: Английский

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TGF-β Signaling from Receptors to Smads

Cold Spring Harbor Perspectives in Biology, Journal Year: 2016, Volume and Issue: 8(9), P. a022061 - a022061

Published: July 22, 2016

Akiko Hata1 and Ye-Guang Chen2 1Cardiovascular Research Institute, University of California, San Francisco, California 94143 2The State Key Laboratory Membrane Biology, Tsinghua-Peking Center for Life Sciences, School Tsinghua University, Beijing 100084, China Correspondence: akiko.hata{at}ucsf.edu; ygchen{at}tsinghua.edu.cn

Language: Английский

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Neuronal calcium signaling: function and dysfunction

Cellular and Molecular Life Sciences, Journal Year: 2014, Volume and Issue: 71(15), P. 2787 - 2814

Published: Jan. 18, 2014

Language: Английский

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The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy

EBioMedicine, Journal Year: 2016, Volume and Issue: 6, P. 42 - 49

Published: April 1, 2016

The incidence of Alzheimer's disease (AD) is growing every day and finding an effective treatment becoming more vital. Amyloid-β (Aβ) has been the focus research for several decades. recent shift in Aβ cascade hypothesis from all to small soluble oligomeric intermediates directing search therapeutics towards toxic mediators disease. Targeting most oligomers may prove be by preventing their spread. Specific targeting shown protect cognition rodent models. Additionally, heterogeneity on seem contradictory until size conformation are taken into account. In this review, we will discuss toxicity relation as well influence inflammation potential oligomer immunotherapy.

Language: Английский

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Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies

Biomolecules, Journal Year: 2016, Volume and Issue: 6(1), P. 6 - 6

Published: Jan. 6, 2016

Abnormal deposition of misprocessed and aggregated proteins is a common final pathway most neurodegenerative diseases, including Alzheimer’s disease (AD). AD characterized by the extraneuronal amyloid β (Aβ) protein in form plaques intraneuronal aggregation microtubule-associated tau filaments. Based on biochemically diverse range pathological proteins, number approaches have been proposed to develop new potential therapeutics. Here we discuss some promising ones: inhibition phosphorylation, proteolysis aggregation, promotion intra- extracellular clearance, stabilization microtubules. We also emphasize need achieve full understanding biological roles post-translational modifications normal tau, as well molecular events responsible for selective neuronal vulnerability pathology its propagation. It concluded that answering key questions relationship between Aβ should lead better nature secondary tauopathies, especially AD, open therapeutic targets strategies.

Language: Английский

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Sampling the conformational space of the catalytic subunit of human γ-secretase

eLife, Journal Year: 2015, Volume and Issue: 4

Published: Dec. 1, 2015

Human γ-secretase is an intra-membrane protease that cleaves many different substrates. Aberrant cleavage of Notch implicated in cancer, while abnormalities cutting amyloid precursor protein lead to Alzheimer's disease. Our previous cryo-EM structure revealed considerable disorder its catalytic subunit presenilin. Here, we describe image classification procedure characterizes molecular plasticity at the secondary level, and apply this method identify three distinct conformations our sample. In one these conformations, additional transmembrane helix visible cannot be attributed known components γ-secretase. addition, present a complex with dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). results reveal how conformational mobility second sixth helices presenilin greatly reduced upon binding DAPT or helix, form basis for new model substrate enters domain.

Language: Английский

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Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies

Progress in Neurobiology, Journal Year: 2013, Volume and Issue: 108, P. 21 - 43

Published: July 11, 2013

Alzheimer's disease (AD) is an age-related devastating neurodegenerative disorder, which severely impacts on the global economic development and healthcare system. Though AD has been studied for more than 100 years since 1906, exact cause(s) pathogenic mechanism(s) remain to be clarified. Also, efficient disease-modifying treatment ideal diagnostic method are unavailable. Perturbed cerebral glucose metabolism, invariant pathophysiological feature of AD, may a critical contributor pathogenesis this disease. In review, we firstly discussed features metabolism in physiological pathological conditions. Then, further reviewed contribution transportation abnormality intracellular catabolism dysfunction pathophysiology, proposed hypothesis that multiple cascades induced by impaired could result neuronal degeneration consequently cognitive deficits patients. Among these processes, altered functional status thiamine brain insulin resistance highly emphasized characterized as major mechanisms. Finally, considering fact patients exhibit hypometabolism possibly due impairments signaling also discuss some potential possibilities uncover biomarkers from abnormal develop drugs targeting at repairing impairment correcting abnormality. We conclude plays role alterations through induction factors such oxidative stress, mitochondrial dysfunction, so forth. To clarify causes, pathogeneses consequences will help break bottleneck current study finding biomarker therapy.

Language: Английский

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Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

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Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease

Neuropeptides, Journal Year: 2015, Volume and Issue: 52, P. 1 - 18

Published: July 4, 2015

Language: Английский

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