title: VPS35 haploinsufficiency increases Alzheimer's disease neuropathology.
abstract: VPS35, a major component of the retromer complex, is important for endosome-to-Golgi retrieval of membrane proteins. Although implicated in Alzheimer'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.
authors: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors: Lei
authors: L
authors: Wen
authors: Fu-Lei
authors: FL
authors: Tang
authors: Yan
authors: Y
authors: Hong
authors: Shi-Wen
authors: SW
authors: Luo
authors: Chun-Lei
authors: CL
authors: Wang
authors: Wanxia
authors: W
authors: He
authors: Chengyong
authors: C
authors: Shen
authors: Ji-Ung
authors: JU
authors: Jung
authors: Fei
authors: F
authors: Xiong
authors: Dae-hoon
authors: DH
authors: Lee
authors: Quan-Guang
authors: QG
authors: Zhang
authors: Darrell
authors: D
authors: Brann
authors: Tae-Wan
authors: TW
authors: Kim
authors: Riqiang
authors: R
authors: Yan
authors: Lin
authors: L
authors: Mei
authors: Wen-Cheng
authors: WC
authors: Xiong
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; C101274:Vps35 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse