Hdl Handle:
http://hdl.handle.net/10675.2/695
Title:
VPS35 haploinsufficiency increases Alzheimerâ s disease neuropathology
Authors:
Wen, Lei; Tang, Fu-Lei; Hong, Yan; Luo, Shi-Wen; Wang, Chun-Lei; He, Wanxia; Shen, Chengyong; Jung, Ji-Ung; Xiong, Fei; Lee, Dae-hoon; Zhang, Quan-Guang; Brann, Darrell W ( 0000-0002-4480-8859 ) ; Kim, Tae-Wan; Yan, Riqiang; Mei, Lin; Xiong, Wen-Cheng
Abstract:
VPS35, a major component of the retromer complex, is important for endosome-to-Golgi retrieval of membrane proteins. Although implicated in Alzheimerâ s disease (AD), how VPS35 regulates AD-associated pathology is unknown. In this paper, we show that hemizygous deletion of Vps35 in the Tg2576 mouse model of AD led to earlier-onset AD-like phenotypes, including cognitive memory deficits, defective long-term potentiation, and impaired postsynaptic glutamatergic neurotransmission in young adult age. These deficits correlated well with an increase of β-amyloid peptide (Aβ) level in the mutant hippocampus. We further demonstrate that VPS35 is predominantly expressed in pyramidal neurons of young adult hippocampus and interacts with BACE1, a protease responsible for Aβ production. Loss of VPS35 function in the mouse hippocampus increased BACE1 activity. Suppression of VPS35 expression in culture decreased BACE1 trans-Golgi localization but enriched it in endosomes. These results demonstrate an essential role for VPS35 in suppression of AD neuropathology and in inhibition of BACE1 activation and Aβ production by promoting BACE1 endosome-to-Golgi retrieval.
Citation:
J Cell Biol. 2011 Nov 28; 195(5):765-779
Issue Date:
28-Nov-2011
URI:
http://hdl.handle.net/10675.2/695
DOI:
10.1083/jcb.201105109
PubMed ID:
22105352
PubMed Central ID:
PMC3257571
Type:
Article
ISSN:
1540-8140
Appears in Collections:
Institute of Molecular Medicine and Genetics: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorWen, Leien_US
dc.contributor.authorTang, Fu-Leien_US
dc.contributor.authorHong, Yanen_US
dc.contributor.authorLuo, Shi-Wenen_US
dc.contributor.authorWang, Chun-Leien_US
dc.contributor.authorHe, Wanxiaen_US
dc.contributor.authorShen, Chengyongen_US
dc.contributor.authorJung, Ji-Ungen_US
dc.contributor.authorXiong, Feien_US
dc.contributor.authorLee, Dae-hoonen_US
dc.contributor.authorZhang, Quan-Guangen_US
dc.contributor.authorBrann, Darrell Wen_US
dc.contributor.authorKim, Tae-Wanen_US
dc.contributor.authorYan, Riqiangen_US
dc.contributor.authorMei, Linen_US
dc.contributor.authorXiong, Wen-Chengen_US
dc.date.accessioned2012-10-26T16:29:35Z-
dc.date.available2012-10-26T16:29:35Z-
dc.date.issued2011-11-28en_US
dc.identifier.citationJ Cell Biol. 2011 Nov 28; 195(5):765-779en_US
dc.identifier.issn1540-8140en_US
dc.identifier.pmid22105352en_US
dc.identifier.doi10.1083/jcb.201105109en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/695-
dc.description.abstractVPS35, a major component of the retromer complex, is important for endosome-to-Golgi retrieval of membrane proteins. Although implicated in Alzheimerâ s disease (AD), how VPS35 regulates AD-associated pathology is unknown. In this paper, we show that hemizygous deletion of Vps35 in the Tg2576 mouse model of AD led to earlier-onset AD-like phenotypes, including cognitive memory deficits, defective long-term potentiation, and impaired postsynaptic glutamatergic neurotransmission in young adult age. These deficits correlated well with an increase of β-amyloid peptide (Aβ) level in the mutant hippocampus. We further demonstrate that VPS35 is predominantly expressed in pyramidal neurons of young adult hippocampus and interacts with BACE1, a protease responsible for Aβ production. Loss of VPS35 function in the mouse hippocampus increased BACE1 activity. Suppression of VPS35 expression in culture decreased BACE1 trans-Golgi localization but enriched it in endosomes. These results demonstrate an essential role for VPS35 in suppression of AD neuropathology and in inhibition of BACE1 activation and Aβ production by promoting BACE1 endosome-to-Golgi retrieval.en_US
dc.rights© 2011 Wen et al.en_US
dc.subject.meshAlzheimer Diseaseen_US
dc.subject.meshAmyloid Precursor Protein Secretasesen_US
dc.subject.meshAmyloid beta-Peptidesen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAspartic Acid Endopeptidasesen_US
dc.subject.meshCerebral Cortexen_US
dc.subject.meshEndosomesen_US
dc.subject.meshHEK293 Cellsen_US
dc.subject.meshHaploinsufficiencyen_US
dc.subject.meshHippocampusen_US
dc.subject.meshHumansen_US
dc.subject.meshMiceen_US
dc.subject.meshVesicular Transport Proteinsen_US
dc.subject.meshtrans-Golgi Networken_US
dc.titleVPS35 haploinsufficiency increases Alzheimerâ s disease neuropathologyen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3257571en_US
dc.contributor.corporatenameInstitute of Molecular Medicine and Genetics-
dc.contributor.corporatenameDepartment of Neurology-

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