An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo

Familial Alzheimer's disease (FAD)-linked mutations in the APP gene occur either within the Aβ-coding region or immediately proximal and are located in exons 16 and 17, which encode Aβ peptides. We have identified an extremely rare, partially penetrant, single nucleotide variant (SNV), rs145081...

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Bibliographic Details
Published in:The Journal of experimental medicine 2021-06, Vol.218 (6)
Main Authors: Zhang, Xulun, Zhang, Can Martin, Prokopenko, Dmitry, Liang, Yingxia, Zhen, Sherri Y, Weigle, Ian Q, Han, Weinong, Aryal, Manish, Tanzi, Rudolph E, Sisodia, Sangram S
Format: Article
Language:English
Subjects:
Alzheimer Disease - genetics
Amyloid beta-Peptides - genetics
Amyloid beta-Protein Precursor - genetics
Animals
Brain - pathology
Cell Line, Tumor
Disease Models, Animal
Exons - genetics
Female
HEK293 Cells
Humans
Male
Mice
Mice, Transgenic - genetics
Mutation - genetics
Neuroscience
Plaque, Amyloid - genetics
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Summary:Familial Alzheimer's disease (FAD)-linked mutations in the APP gene occur either within the Aβ-coding region or immediately proximal and are located in exons 16 and 17, which encode Aβ peptides. We have identified an extremely rare, partially penetrant, single nucleotide variant (SNV), rs145081708, in APP that corresponds to a Ser198Pro substitution in exon 5. We now report that in stably transfected cells, expression of APP harboring the S198P mutation (APPS198P) leads to elevated production of Aβ peptides by an unconventional mechanism in which the folding and exit of APPS198P from the endoplasmic reticulum is accelerated. More importantly, coexpression of APP S198P and the FAD-linked PS1ΔE9 variant in the brains of male and female transgenic mice leads to elevated steady-state Aβ peptide levels and acceleration of Aβ deposition compared with age- and gender-matched mice expressing APP and PS1ΔE9. This is the first AD-linked mutation in APP present outside of exons 16 and 17 that enhances Aβ production and deposition.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20210313