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Phosphatidylinositol‐4‐phosphate 5‐kinase type 1α attenuates Aβ production by promoting non‐amyloidogenic processing of amyloid precursor protein
Author(s) -
Wu PoFan,
Bhore Noopur,
Lee YenLurk,
Chou JuYun,
Chen YunWen,
Wu PeiYi,
Hsu WenMing,
Lee Hsinyu,
Huang YiShuian,
Lu PeiJung,
Liao YungFeng
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000113r
Subject(s) - amyloid precursor protein , phosphatidylinositol , microbiology and biotechnology , endosome , amyloid precursor protein secretase , chemistry , proteolysis , p3 peptide , kinase , biochemistry , alzheimer's disease , intracellular , biology , medicine , disease , enzyme
Alzheimer's disease (AD) is characterized by a chronic decline in cognitive function and is pathologically typified by cerebral deposition of amyloid‐β peptide (Aβ). The production of Aβ is mediated by sequential proteolysis of amyloid precursor protein (APP) by β‐ and γ‐secretases, and has been implicated as the essential determinant of AD pathology. Previous studies have demonstrated that the level of phosphatidylinositol‐4,5‐bisphosphate [PI(4,5)P2] in the membrane may potentially modulate Aβ production. Given that PI(4,5)P2 is produced by type 1 phosphatidylinositol‐4‐phosphate 5‐kinases (PIP5Ks), we sought to determine whether the level of PIP5K type Iα (PIP5K1A) can affect production of Aβ by modulating the lipid composition of the membrane. Using a HEK‐derived cell line that constitutively expresses yellow fluorescent protein‐tagged APP (APP‐YFP), we demonstrated that overexpression of PIP5K1A results in significant enhancement of non‐amyloidogenic APP processing and a concomitant suppression of the amyloidogenic pathway, leading to a marked decrease in secreted Aβ. Consistently, cells overexpressing PIP5K1A exhibited a significant redistribution of APP‐YFP from endosomal compartments to the cell surface. Our findings suggest that PIP5K1A may play a critical role in governing Aβ production by modulating membrane distribution of APP, and as such, the pathway may be a valuable therapeutic target for AD.