Retromer disruption promotes amyloidogenic APP processing

Retromer deficiency has been implicated in sporadic AD and animals deficient in retromer components exhibit pronounced neurodegeneration. Because retromer performs retrograde transport from the endosome to the Golgi apparatus and neuronal Aβ is found in late endosomal compartments, we speculated tha...

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Main Authors: Christopher P. Sullivan, Anthony G. Jay, Edward C. Stack, Maria Pakaluk, Erin Wadlinger, Richard E. Fine, John M. Wells, Peter J. Morin
Format: Article
Language:English
Published: Elsevier 2011-08-01
Series:Neurobiology of Disease
Subjects:
APP
Online Access:http://www.sciencedirect.com/science/article/pii/S0969996111001197
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language English
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author Christopher P. Sullivan
Anthony G. Jay
Edward C. Stack
Maria Pakaluk
Erin Wadlinger
Richard E. Fine
John M. Wells
Peter J. Morin
spellingShingle Christopher P. Sullivan
Anthony G. Jay
Edward C. Stack
Maria Pakaluk
Erin Wadlinger
Richard E. Fine
John M. Wells
Peter J. Morin
Retromer disruption promotes amyloidogenic APP processing
Neurobiology of Disease
Retromer
Vps35
APP

Exosome
Endosome
author_facet Christopher P. Sullivan
Anthony G. Jay
Edward C. Stack
Maria Pakaluk
Erin Wadlinger
Richard E. Fine
John M. Wells
Peter J. Morin
author_sort Christopher P. Sullivan
title Retromer disruption promotes amyloidogenic APP processing
title_short Retromer disruption promotes amyloidogenic APP processing
title_full Retromer disruption promotes amyloidogenic APP processing
title_fullStr Retromer disruption promotes amyloidogenic APP processing
title_full_unstemmed Retromer disruption promotes amyloidogenic APP processing
title_sort retromer disruption promotes amyloidogenic app processing
publisher Elsevier
series Neurobiology of Disease
issn 1095-953X
publishDate 2011-08-01
description Retromer deficiency has been implicated in sporadic AD and animals deficient in retromer components exhibit pronounced neurodegeneration. Because retromer performs retrograde transport from the endosome to the Golgi apparatus and neuronal Aβ is found in late endosomal compartments, we speculated that retromer malfunction might enhance amyloidogenic APP processing by promoting interactions between APP and secretase enzymes in late endosomes. We have evaluated changes in amyloid precursor protein (APP) processing and trafficking as a result of disrupted retromer activity by knockdown of Vps35, a vacuolar sorting protein that is an essential component of the retromer complex. Knocking down retromer activity produced no change in the quantity or cellular distribution of total cellular APP and had no affect on internalization of cell-surface APP. Retromer deficiency did, however, increase the ratio of secreted Aβ42:Aβ40 in HEK-293 cells over-expressing APP695, due primarily to a decrease in Aβ40 secretion. Recent studies suggest that the retromer-trafficked protein, Wntless, is secreted at the synapse in exosome vesicles and that these same vesicles contain Aβ. We therefore hypothesized that retromer deficiency may be associated with altered exosomal secretion of APP and/or secretase fragments. Holo-APP, Presenilin and APP C-terminal fragments were detected in exosomal vesicles secreted from HEK-293 cells. Levels of total APP C-terminal fragments were significantly increased in exosomes secreted by retromer deficient cells. These data suggest that reduced retromer activity can mimic the effects of familial AD Presenilin mutations on APP processing and promote export of amyloidogenic APP derivatives.
topic Retromer
Vps35
APP

Exosome
Endosome
url http://www.sciencedirect.com/science/article/pii/S0969996111001197
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AT erinwadlinger retromerdisruptionpromotesamyloidogenicappprocessing
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spelling doaj-f8abd9a832864fe0913fb4fd225707f02021-03-22T12:36:49ZengElsevierNeurobiology of Disease1095-953X2011-08-01432338345Retromer disruption promotes amyloidogenic APP processingChristopher P. Sullivan0Anthony G. Jay1Edward C. Stack2Maria Pakaluk3Erin Wadlinger4Richard E. Fine5John M. Wells6Peter J. Morin7Corresponding author at: Bedford VA Medical Center, GRECC (182B), 200 Springs Rd., Bedford, MA 01730, USA. Fax: +1 781 687 3832.; Geriatric Research, Education, and Clinical Center, Edith Nourse Rogers Memorial Veteran's Administration Hospital, Bedford, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USAGeriatric Research, Education, and Clinical Center, Edith Nourse Rogers Memorial Veteran's Administration Hospital, Bedford, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USAGeriatric Research, Education, and Clinical Center, Edith Nourse Rogers Memorial Veteran's Administration Hospital, Bedford, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USAGeriatric Research, Education, and Clinical Center, Edith Nourse Rogers Memorial Veteran's Administration Hospital, Bedford, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USAGeriatric Research, Education, and Clinical Center, Edith Nourse Rogers Memorial Veteran's Administration Hospital, Bedford, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USAGeriatric Research, Education, and Clinical Center, Edith Nourse Rogers Memorial Veteran's Administration Hospital, Bedford, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USAGeriatric Research, Education, and Clinical Center, Edith Nourse Rogers Memorial Veteran's Administration Hospital, Bedford, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USAGeriatric Research, Education, and Clinical Center, Edith Nourse Rogers Memorial Veteran's Administration Hospital, Bedford, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USARetromer deficiency has been implicated in sporadic AD and animals deficient in retromer components exhibit pronounced neurodegeneration. Because retromer performs retrograde transport from the endosome to the Golgi apparatus and neuronal Aβ is found in late endosomal compartments, we speculated that retromer malfunction might enhance amyloidogenic APP processing by promoting interactions between APP and secretase enzymes in late endosomes. We have evaluated changes in amyloid precursor protein (APP) processing and trafficking as a result of disrupted retromer activity by knockdown of Vps35, a vacuolar sorting protein that is an essential component of the retromer complex. Knocking down retromer activity produced no change in the quantity or cellular distribution of total cellular APP and had no affect on internalization of cell-surface APP. Retromer deficiency did, however, increase the ratio of secreted Aβ42:Aβ40 in HEK-293 cells over-expressing APP695, due primarily to a decrease in Aβ40 secretion. Recent studies suggest that the retromer-trafficked protein, Wntless, is secreted at the synapse in exosome vesicles and that these same vesicles contain Aβ. We therefore hypothesized that retromer deficiency may be associated with altered exosomal secretion of APP and/or secretase fragments. Holo-APP, Presenilin and APP C-terminal fragments were detected in exosomal vesicles secreted from HEK-293 cells. Levels of total APP C-terminal fragments were significantly increased in exosomes secreted by retromer deficient cells. These data suggest that reduced retromer activity can mimic the effects of familial AD Presenilin mutations on APP processing and promote export of amyloidogenic APP derivatives.http://www.sciencedirect.com/science/article/pii/S0969996111001197RetromerVps35APPAβExosomeEndosome