The APMAP interactome reveals new modulators of APP processing and beta-amyloid production that are altered in Alzheimer's disease.

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Serval ID
serval:BIB_F505E5A17862
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The APMAP interactome reveals new modulators of APP processing and beta-amyloid production that are altered in Alzheimer's disease.
Journal
Acta neuropathologica communications
Author(s)
Gerber H., Mosser S., Boury-Jamot B., Stumpe M., Piersigilli A., Goepfert C., Dengjel J., Albrecht U., Magara F., Fraering P.C.
ISSN
2051-5960 (Electronic)
ISSN-L
2051-5960
Publication state
Published
Issued date
31/01/2019
Peer-reviewed
Oui
Volume
7
Number
1
Pages
13
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
The adipocyte plasma membrane-associated protein APMAP is expressed in the brain where it associates with γ-secretase, a protease responsible for the generation of the amyloid-β peptides (Aβ) implicated in the pathogenesis of Alzheimer's disease (AD). In this study, behavioral investigations revealed spatial learning and memory deficiencies in our newly generated mouse line lacking the protein APMAP. In a mouse model of AD, the constitutive deletion of APMAP worsened the spatial memory phenotype and led to increased Aβ production and deposition into senile plaques. To investigate at the molecular level the neurobiological functions of APMAP (memory and Aβ formation) and a possible link with the pathological hallmarks of AD (memory impairment and Aβ pathology), we next developed a procedure for the high-grade purification of cellular APMAP protein complexes. The biochemical characterization of these complexes revealed a series of new APMAP interactomers. Among these, the heat shock protein HSPA1A and the cation-dependent mannose-6-phosphate receptor (CD-M6PR) negatively regulated APP processing and Aβ production, while clusterin, calnexin, arginase-1, PTGFRN and the cation-independent mannose-6-phosphate receptor (CI-M6PR/IGF2R) positively regulated APP and Aβ production. Several of the newly identified APMAP interactomers contribute to the autophagy-lysosome system, further supporting an emergent agreement that this pathway can modulate APP metabolism and Aβ generation. Importantly, we have also demonstrated increased alternative splicing of APMAP and lowered levels of the Aβ controllers HSPA1A and CD-M6PR in human brains from neuropathologically verified AD cases.
Keywords
Aged, Aged, 80 and over, Alzheimer Disease/metabolism, Amyloid beta-Peptides/metabolism, Amyloid beta-Protein Precursor/metabolism, Animals, Brain/metabolism, CHO Cells, Cricetulus, Female, Frontal Lobe/metabolism, HEK293 Cells, Humans, Male, Membrane Glycoproteins/genetics, Membrane Glycoproteins/metabolism, Mice, Inbred C57BL, Mice, Knockout, Proteome, Spatial Memory/physiology, APMAP interactome, APMAP-KO, Alternative splicing, Alzheimer’s disease, Aβ production, Learning and memory, Neurodegeneration
Pubmed
Web of science
Open Access
Yes
Create date
07/02/2019 12:19
Last modification date
27/04/2020 6:20
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