Presenilin-1 Regulates Intracellular Trafficking and Cell Surface Delivery of β-Amyloid Precursor Protein

Abstract

Presenilins (PS1/PS2) play a critical role in proteolysis of ␤-amyloid precursor protein (␤APP) to generate ␤-amyloid, a peptide important in the pathogenesis of Alzheimer's disease. Nevertheless, several regulatory functions of PS1 have also been reported. Here we demonstrate, in neuroblastoma cells, that PS1 regulates the biogenesis of ␤APP-containing vesicles from the transGolgi network and the endoplasmic reticulum. PS1 deficiency or the expression of loss-of-function variants leads to robust vesicle formation, concomitant with increased maturation and/or cell surface accumulation of ␤APP. In contrast, release of vesicles containing ␤APP is impaired in familial Alzheimer's disease (FAD)-linked PS1 mutant cells, resulting in reduced ␤APP delivery to the cell surface. Moreover, diminution of surface ␤APP is profound at axonal terminals in neurons expressing a PS1 FAD variant. These results suggest that PS1 regulation of ␤APP trafficking may represent an alternative mechanism by which FAD-linked PS1 variants modulate ␤APP processing.Alzheimer's disease (AD) 1 is characterized by the excessive generation and accumulation of ␤-amyloid peptides (A␤). The amyloidogenic A␤ peptide is proteolytically derived from the ␤-amyloid precursor protein (␤APP) within the secretory pathway by distinct enzymatic activities known as ␤-and ␥-secretase (1, 2). Full-length ␤APP is synthesized in the endoplasmic reticulum (ER) and transported through the Golgi apparatus. The major population of secreted A␤ peptides is generated within the trans-Golgi network (TGN) (3-5), also the major site of ␤APP residence in neurons at steady state. ␤APP can be transported in TGN-derived secretory vesicles to the cell surface if not first proteolyzed to A␤ or an intermediate metabolite.At the plasma membrane ␤APP is either cleaved to produce a soluble molecule, s␤APP (6) or, alternatively, reinternalized within clathrin-coated vesicles to an endosomal/lysosomal degradation pathway (7,8). Thus, the distribution of ␤APP between the TGN and cell surface has a direct influence upon the relative generation of s␤APP versus A␤. This phenomenon makes delineation of the mechanisms responsible for regulating ␤APP trafficking from the TGN relevant to understanding the pathogenesis of AD.Expression of autosomal dominant variants of either ␤APP, presenilin 1 (PS1), or presenilin 2 (PS2) results in increased A␤42 production and predispose individuals to early onset familial Alzheimer's disease (FAD) (9 -11). Presenilins (PSs), multitransmembrane proteins, accumulate as endoproteolyzed heterodimers of N-and C-terminal fragments and associate with other membrane proteins (e.g. nicastrin, APH-1, and PEN-2) to form high molecular weight complexes (9,(12)(13)(14)(15)(16). Several lines of evidence suggest that presenilin complexes play a crucial role in intramembranous ␥-secretase cleavage of type I membrane proteins including ␤APP and the signaling receptor, Notch-1. For example, genetic ablation of PS1, PS2, or other components of the PS complex dramatically im...

Regulation of tyrosinase trafficking and processing by presenilins: Partial loss of function by familial Alzheimer's disease mutation

“…Indeed, Western blot analysis showed normal expression of AP3 subunits in PS-null melanocytes (data not shown). The fact that the APP C terminus does not have the dileucine motif and that PS was reported to affect APP trafficking to plasma membrane or endocytosis not known to mediate Tyr routing further corroborate with this notion (10,11). Further work is required to identify the mechanism where by PS regulates the trafficking of these diverse type I membrane proteins.…”

“…PS1 deficiency has been reported to result in aberrant trafficking and maturation of APP (10,11), Notch (12,13), tyrosine kinase receptor TrkB (14), ␤-and ␦-catenin (15,16), and nicastrin (17)(18)(19). Reports by Esselens et al (20) and Wilson et al (21) implicated a role of PS1 in the turnover of telencephalin and ␣-and ␤-synucleins, respectively.…”

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

“…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).…”

Magnesium in the Central Nervous System

“…Magnesium supplementation may be a safe and well--tolerated option for migraine prophylaxis in the prevention of paediatric migraine. However, while a double--blind placebo--controlled, randomized trial of patients aged 3 to 17 years found a statistically significant downward trend in headache frequency in those treated with magnesium oxide, the difference in the slopes of the two lines was not statistically significant (Wang et al, 2003). It could therefore not be determined if oral magnesium was superior to placebo in preventing frequent migraines in children and adolescents.…”

“…Thus, delineation of how the intracellular trafficking of these secretases and APP are regulated is important for understanding AD pathogenesis. Although APP trafficking is regulated by multiple factors including PS1 (Cai et al, 2003), a major component of the γ--secretase complex, and phospholipase D1, a phospholipid--modifying enzyme, APP can reciprocally regulate PS1 trafficking. APP deficiency results in faster transport of PS1 from the trans--Golgi network to the cell surface and increased steady state levels of PS1 at the cell surface, which can be reversed by restoring APP levels (Liu et al, 2009 (Yu et al, 2010).…”