Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Alpha Attenuates A Beta Production By Promoting Non-Amyloidogenic Processing Of Amyloid Precursor Protein

Alzheimer's disease (AD) is characterized by a chronic decline in cognitive function and is pathologically typified by cerebral deposition of amyloid-beta peptide (A beta). The production of A beta is mediated by sequential proteolysis of amyloid precursor protein (APP) by beta- and gamma-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 A beta 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 I alpha (PIP5K1A) can affect production of A beta 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 A beta. 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 A beta production by modulating membrane distribution of APP, and as such, the pathway may be a valuable therapeutic target for AD.