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

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.

Fission Yeast PUF Proteins Puf3 and Puf4 Are Novel Regulators of PI4P5K Signaling

“…Phosphatidylinositol-4-phosphate 5-kinase (PI4P5K) acts as a key enzyme to generate PI(4,5) P 2 by phosphorylating the five position on the inositol ring of phosphatidylinositol 4-phosphate (PI(4) P). It was reported that PI4P5K regulates Ca 2+ signaling, cytoskeletal dynamics, and membrane trafficking, [4][5][6][7] and is related to Alzheimer's disease, pain regulation, and cancer cell proliferation, [8][9][10][11] thus elucidation of the regulatory mechanisms of PI4P5K is important biologically and pharmacologically.…”