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  1. AU="Niederst, Emily D"
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  1. Article ; Online: Axonal amyloid precursor protein and its fragments undergo somatodendritic endocytosis and processing.

    Niederst, Emily D / Reyna, Sol M / Goldstein, Lawrence S B

    Molecular biology of the cell

    2015  Volume 26, Issue 2, Page(s) 205–217

    Abstract: Deposition of potentially neurotoxic Aβ fragments derived from amyloid precursor protein (APP) at synapses may be a key contributor to Alzheimer's disease. However, the location(s) of proteolytic processing and subsequent secretion of APP fragments from ... ...

    Abstract Deposition of potentially neurotoxic Aβ fragments derived from amyloid precursor protein (APP) at synapses may be a key contributor to Alzheimer's disease. However, the location(s) of proteolytic processing and subsequent secretion of APP fragments from highly compartmentalized, euploid neurons that express APP and processing enzymes at normal levels is not well understood. To probe the behavior of endogenous APP, particularly in human neurons, we developed a system using neurons differentiated from human embryonic stem cells, cultured in microfluidic devices, to enable direct biochemical measurements from axons. Using human or mouse neurons in these devices, we measured levels of Aβ, sAPPα, and sAPPβ secreted solely from axons. We found that a majority of the fragments secreted from axons were processed in the soma, and many were dependent on somatic endocytosis for axonal secretion. We also observed that APP and the β-site APP cleaving enzyme were, for the most part, not dependent on endocytosis for axonal entry. These data establish that axonal entry and secretion of APP and its proteolytic processing products traverse different pathways in the somatodendritic compartment before axonal entry.
    MeSH term(s) Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Axons/metabolism ; Benzodiazepinones/pharmacology ; Cell Differentiation ; Cell Line ; Cells, Cultured ; Dendrites/metabolism ; Embryonic Stem Cells/metabolism ; Endocytosis/drug effects ; Endocytosis/physiology ; Humans ; Hydrazones/pharmacology ; Luminescent Proteins/genetics ; Luminescent Proteins/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Microfluidic Analytical Techniques ; Microscopy, Confocal ; Oligopeptides/pharmacology ; Peptide Fragments/metabolism ; Signal Transduction/drug effects
    Chemical Substances 2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Benzodiazepinones ; Hydrazones ; Luminescent Proteins ; N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide ; OM99-2 ; Oligopeptides ; Peptide Fragments ; Amyloid Precursor Protein Secretases (EC 3.4.-)
    Language English
    Publishing date 2015-01-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E14-06-1049
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2853: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 410: Show issues

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  2. Article ; Online: Revealing nanostructures in brain tissue via protein decrowding by iterative expansion microscopy.

    Sarkar, Deblina / Kang, Jinyoung / Wassie, Asmamaw T / Schroeder, Margaret E / Peng, Zhuyu / Tarr, Tyler B / Tang, Ai-Hui / Niederst, Emily D / Young, Jennie Z / Su, Hanquan / Park, Demian / Yin, Peng / Tsai, Li-Huei / Blanpied, Thomas A / Boyden, Edward S

    Nature biomedical engineering

    2022  Volume 6, Issue 9, Page(s) 1057–1073

    Abstract: Many crowded biomolecular structures in cells and tissues are inaccessible to labelling antibodies. To understand how proteins within these structures are arranged with nanoscale precision therefore requires that these structures be decrowded before ... ...

    Abstract Many crowded biomolecular structures in cells and tissues are inaccessible to labelling antibodies. To understand how proteins within these structures are arranged with nanoscale precision therefore requires that these structures be decrowded before labelling. Here we show that an iterative variant of expansion microscopy (the permeation of cells and tissues by a swellable hydrogel followed by isotropic hydrogel expansion, to allow for enhanced imaging resolution with ordinary microscopes) enables the imaging of nanostructures in expanded yet otherwise intact tissues at a resolution of about 20 nm. The method, which we named 'expansion revealing' and validated with DNA-probe-based super-resolution microscopy, involves gel-anchoring reagents and the embedding, expansion and re-embedding of the sample in homogeneous swellable hydrogels. Expansion revealing enabled us to use confocal microscopy to image the alignment of pre-synaptic calcium channels with post-synaptic scaffolding proteins in intact brain circuits, and to uncover periodic amyloid nanoclusters containing ion-channel proteins in brain tissue from a mouse model of Alzheimer's disease. Expansion revealing will enable the further discovery of previously unseen nanostructures within cells and tissues.
    MeSH term(s) Animals ; Brain/metabolism ; Calcium Channels/metabolism ; DNA/metabolism ; Hydrogels ; Mice ; Microscopy/methods ; Nanostructures ; Proteins/metabolism
    Chemical Substances Calcium Channels ; Hydrogels ; Proteins ; DNA (9007-49-2)
    Language English
    Publishing date 2022-08-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ISSN 2157-846X
    ISSN (online) 2157-846X
    DOI 10.1038/s41551-022-00912-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: UV irradiation accelerates amyloid precursor protein (APP) processing and disrupts APP axonal transport.

    Almenar-Queralt, Angels / Falzone, Tomas L / Shen, Zhouxin / Lillo, Concepcion / Killian, Rhiannon L / Arreola, Angela S / Niederst, Emily D / Ng, Kheng S / Kim, Sonia N / Briggs, Steven P / Williams, David S / Goldstein, Lawrence S B

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2014  Volume 34, Issue 9, Page(s) 3320–3339

    Abstract: Overexpression and/or abnormal cleavage of amyloid precursor protein (APP) are linked to Alzheimer's disease (AD) development and progression. However, the molecular mechanisms regulating cellular levels of APP or its processing, and the physiological ... ...

    Abstract Overexpression and/or abnormal cleavage of amyloid precursor protein (APP) are linked to Alzheimer's disease (AD) development and progression. However, the molecular mechanisms regulating cellular levels of APP or its processing, and the physiological and pathological consequences of altered processing are not well understood. Here, using mouse and human cells, we found that neuronal damage induced by UV irradiation leads to specific APP, APLP1, and APLP2 decline by accelerating their secretase-dependent processing. Pharmacological inhibition of endosomal/lysosomal activity partially protects UV-induced APP processing implying contribution of the endosomal and/or lysosomal compartments in this process. We found that a biological consequence of UV-induced γ-secretase processing of APP is impairment of APP axonal transport. To probe the functional consequences of impaired APP axonal transport, we isolated and analyzed presumptive APP-containing axonal transport vesicles from mouse cortical synaptosomes using electron microscopy, biochemical, and mass spectrometry analyses. We identified a population of morphologically heterogeneous organelles that contains APP, the secretase machinery, molecular motors, and previously proposed and new residents of APP vesicles. These possible cargoes are enriched in proteins whose dysfunction could contribute to neuronal malfunction and diseases of the nervous system including AD. Together, these results suggest that damage-induced APP processing might impair APP axonal transport, which could result in failure of synaptic maintenance and neuronal dysfunction.
    MeSH term(s) Amyloid beta-Protein Precursor/deficiency ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Axonal Transport/radiation effects ; Axons/drug effects ; Axons/metabolism ; Axons/radiation effects ; Axons/ultrastructure ; Cells, Cultured ; Embryo, Mammalian ; Gene Expression Regulation/radiation effects ; Hippocampus/cytology ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroblastoma/pathology ; Neurons/cytology ; Neurons/radiation effects ; Presenilin-1/deficiency ; Presenilin-2/deficiency ; Transfection ; Ultraviolet Rays
    Chemical Substances Amyloid beta-Protein Precursor ; PSEN1 protein, human ; PSEN2 protein, human ; Presenilin-1 ; Presenilin-2
    Language English
    Publishing date 2014-02-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.1503-13.2014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1668: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  4. Article ; Online: SMN regulates axonal local translation via miR-183/mTOR pathway.

    Kye, Min Jeong / Niederst, Emily D / Wertz, Mary H / Gonçalves, Inês do Carmo G / Akten, Bikem / Dover, Katarzyna Z / Peters, Miriam / Riessland, Markus / Neveu, Pierre / Wirth, Brunhilde / Kosik, Kenneth S / Sardi, S Pablo / Monani, Umrao R / Passini, Marco A / Sahin, Mustafa

    Human molecular genetics

    2014  Volume 23, Issue 23, Page(s) 6318–6331

    Abstract: Reduced expression of SMN protein causes spinal muscular atrophy (SMA), a neurodegenerative disorder leading to motor neuron dysfunction and loss. However, the molecular mechanisms by which SMN regulates neuronal dysfunction are not fully understood. ... ...

    Abstract Reduced expression of SMN protein causes spinal muscular atrophy (SMA), a neurodegenerative disorder leading to motor neuron dysfunction and loss. However, the molecular mechanisms by which SMN regulates neuronal dysfunction are not fully understood. Here, we report that reduced SMN protein level alters miRNA expression and distribution in neurons. In particular, miR-183 levels are increased in neurites of SMN-deficient neurons. We demonstrate that miR-183 regulates translation of mTor via direct binding to its 3' UTR. Interestingly, local axonal translation of mTor is reduced in SMN-deficient neurons, and this can be recovered by miR-183 inhibition. Finally, inhibition of miR-183 expression in the spinal cord of an SMA mouse model prolongs survival and improves motor function of Smn-mutant mice. Together, these observations suggest that axonal miRNAs and the mTOR pathway are previously unidentified molecular mechanisms contributing to SMA pathology.
    MeSH term(s) 3' Untranslated Regions ; Animals ; Axons/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Muscular Atrophy, Spinal/metabolism ; Muscular Atrophy, Spinal/pathology ; Neurons/metabolism ; Primary Cell Culture ; Protein Biosynthesis ; RNA, Messenger/metabolism ; Rats, Sprague-Dawley ; Survival of Motor Neuron 1 Protein/genetics ; Survival of Motor Neuron 1 Protein/metabolism ; TOR Serine-Threonine Kinases/biosynthesis ; TOR Serine-Threonine Kinases/genetics
    Chemical Substances 3' Untranslated Regions ; MIRN183 microRNA, rat ; MicroRNAs ; RNA, Messenger ; Smn1 protein, rat ; Survival of Motor Neuron 1 Protein ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, rat (EC 2.7.1.1)
    Language English
    Publishing date 2014-07-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddu350
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3469: Show issues Location:
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