Effects of PS1 Deficiency on Membrane Protein Trafficking in Neurons

Abstract

We have examined the trafficking and metabolism of the beta-amyloid precursor protein (APP), an APP homolog (APLP1), and TrkB in neurons that lack PS1. We report that PS1-deficient neurons fail to secrete Abeta, and that the rate of appearance of soluble APP derivatives in the conditioned medium is increased. Remarkably, carboxyl-terminal fragments (CTFs) derived from APP and APLP1 accumulate in PS1-deficient neurons. Hence, PS1 plays a role in promoting intramembrane cleavage and/or degradation of membrane-bound CTFs. Moreover, the maturation of TrkB and BDNF-inducible TrkB autophosphorylation is severely compromised in neurons lacking PS1. We conclude that PS1 plays an essential role in modulating trafficking and metabolism of a selected set of membrane and secretory proteins in neurons.

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

“…PIP 2 has been shown to play a role in a variety of cell functions, including ion channel modulation, rearrangement of cytoskeleton, and membrane protein trafficking (26). Intriguingly, cellular phenotypes in PIP 2 -compromised cells are reminiscent of those observed in cells expressing FADassociated presenilin mutations, e.g., ion channel and trafficking deficits (15). The potential role of presenilin in PIP 2 metabolism can be further evidenced by occurrence of PS1 in PIP 2 -enriched subcellular compartments, including lipid rafts (44), phagocytic cups (19), lamellipodia (45), and adherent junctions (18).…”

“…Increasing evidence indicates that the presenilins are involved in several additional, ␥-secretase-independent cellular functions including Wnt and Akt signaling (12)(13)(14), membrane protein trafficking (15), ion channel regulation (16,17), and cell junction organization (18). Two of the most consistent cellular changes associated with both PS1 and PS2 FAD-associated mutations include ion channel dysfunction, such as defects in capacitative Ca 2ϩ entry (CCE) (16,17) and membrane trafficking defects, including diminished cell surface delivery of APP (15,(19)(20)(21).…”

“…Two of the most consistent cellular changes associated with both PS1 and PS2 FAD-associated mutations include ion channel dysfunction, such as defects in capacitative Ca 2ϩ entry (CCE) (16,17) and membrane trafficking defects, including diminished cell surface delivery of APP (15,(19)(20)(21). These A␤42-independent cellular changes may also contribute to the onset and/or neuropathological characteristics of presenilindependent FAD (22).…”

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

“…It also raises the question as to whether other biochemical impairments or behavioral alterations present in APP V717I transgene mice can be reverted in their double transgenic mice. Regarding that PS1 has pleiotropic roles in brain cell functions, e.g., Notch (Naruse et al, 1998;Song et al, 1999) and N-cadherin (Marambaud et al, 2003) processing, it needs to be answered whether the observed learning deficits of the conditional PS1 knockout mice used in their studies were produced solely by hCTF99, by other PS1-cleaved products, or by the lack of a PS1-dependent physiology.…”

Association of γ-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes

“…Genetic mutations in the APP, PSEN1, and PSEN2 genes are responsible for familial early-onset Alzheimer's disease (5,6). PSEN1 and PSEN2 encode polytopic membrane proteins presenilin 1 (PS1) and PS2, respectively, which as components of the ␥-secretase complex play essential role in A␤ production (7,8). Considerable evidence suggests that familial Alzheimer's disease-linked PS1 and PS2 (PS) variants exert their pathogenic influence by selectively elevating the levels of highly fibrillogenic A␤42 peptides (2,4).…”