Phosphatidylinositol-4-phosphate 5-kinase type 1α attenuates Aβ production by promoting non-amyloidogenic processing of amyloid precursor protein

Po Fan Wu, Noopur Bhore, Yen Lurk Lee, Ju Yun Chou, Yun Wen Chen, Pei Yi Wu, Wen Ming Hsu, Hsinyu Lee, Yi Shuian Huang, Pei Jung Lu, Yung Feng Liao

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)12127-12146
Number of pages20
JournalFASEB Journal
Volume34
Issue number9
DOIs
Publication statusPublished - 2020 Sep 1

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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