Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system

Abstract

Defects in endosomal sorting have been implicated in Alzheimer’s disease (AD). Endosomal traffic is largely controlled by phosphatidylinositol-3-phosphate (PI3P), a phosphoinositide synthesized primarily by lipid kinase Vps34. Here we show that PI3P is selectively deficient in brain tissue from humans with AD and AD mouse models. Silencing Vps34 causes an enlargement of neuronal endosomes, enhances the amyloidogenic processing of amyloid precursor protein (APP) in these organelles and reduces APP sorting to intraluminal vesicles. This trafficking phenotype is recapitulated by silencing components of the ESCRT pathway, including the PI3P effector Hrs and Tsg101. APP is ubiquitinated, and interfering with this process by targeted mutagenesis alters sorting of APP to the intraluminal vesicles of endosomes and enhances amyloid-beta peptide generation. In addition to establishing PI3P deficiency as a contributing factor in AD, these results clarify the mechanisms of APP trafficking through the endosomal system in normal and pathological states.

Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus

“…2F). As previously observed, Rab5 and EEA1 colocalized on enlarged endosomes in Vps34-deficient cells (Johnson et al, 2006;Morel et al, 2013), and this localization was unaffected by wortmannin ( percentage of EEA1 colocalizing with Rab5 was 75.9 with DMSO and 64.2 with wortmannin, n=4) (Fig. 2E,F).…”

Classes of phosphoinositide 3-kinases at a glance

“…In addition, low levels of PtdIns(3)P in brain have been found in humans affected with Alzheimer's disease (Morel et al, 2013), and co-expression of Vps15 and Vps34 could suppress aspects of Danon autophagic vacuolar myopathy (AVM) disease in human patient muscle cells (Nemazanyy et al, 2013).…”

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

“…Key to this process is the phosphatidylinositol-3-phosphate effector Hrs, an early endosome-associated ubiquitininteracting motif-containing protein that plays a central role in directing traffi cking of membrane cargo proteins from early endosomes to luminal vesicles of multivesicular bodies (MVBs) for eventual degradation in the lysosome. Knockdown of Hrs or other proteins required for the transport of A ␤ PP from early endosomes to luminal vesicles of MVBs results in increased amyloidogenic processing ( 86 ), supporting the general hypothesis that any defect that keeps A ␤ PP and its processing enzyme, BACE1, in endosomes will increase A ␤ production and drive pathology ( 87 ). Intriguingly, a recent screen for ubiquitinated proteins specifi cally recognized by Hrs identifi ed 48 targets, among which were A ␤ PP and PLD3 ( 88 ).…”