Presenilins Regulate The Cellular Level Of Tumor Suppressor PTEN

Alzheimer's disease (AD) is characterized byβ-amyloid plaques consisting ofβ-amyloid ( Aβ) peptides and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Aβis proteolytically derived from its precursor protein through cleavages byβ-secretase andγ-secretase complex comprising presenilins (PS, PS1/PS2), nicastrin, APH-1 and PEN-2. PS1 is also known to activate the PI3K/Akt cell survival pathway in aγ-secretase-independent manner. The tumor suppressor PTEN, which antagonizes the PI3K/Akt pathway, has increasingly been recognized to play a key role in neural functions and its level found reduced in AD brains. Here, we demonstrate that the protein level of PTEN is dramatically reduced in cultured cells and embryonic tissues deficient of PS, and in the cortical neurons of PS1/PS2 conditional double knockout mice. Restoration of PS in PS deficient cells reverses the reduction of PTEN. Regulation of PTEN by PS is independent of the PS/γ-secretase activity since impairedγ-secretase by theγ-secretase inhibitor treatment or due to nicastrin deficiency has little effect on the protein level of PTEN. Our data suggest an important role for PS in signaling pathways involving PI3K/Akt and PTEN that are crucial for physiological functions and the pathogenesis of multiple diseases.