A Paired RNAi and RabGAP Overexpression Screen Identifies Rab11 as a Regulator of β-Amyloid Production

Abstract

Summary Alzheimer’s disease (AD) is characterized by cerebral deposition of β-amyloid (Aβ) peptides, which are generated from amyloid precursor protein (APP) by β- and γ-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls Aβ levels is unclear. Here, we performed an RNAi screen of all human Rab-GTPases, which regulate membrane trafficking, complemented with a Rab-GTPase-activating protein screen, and present a road map of the membrane-trafficking events regulating Aβ production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled β-secretase endosomal recycling to the plasma membrane and thus affected Aβ production. Exome sequencing revealed a significant genetic association of Rab11A with late-onset AD, and network analysis identified Rab11A and Rab11B as components of the late-onset AD risk network, suggesting a causal link between Rab11 and AD. Our results reveal trafficking pathways that regulate Aβ levels and show how systems biology approaches can unravel the molecular complexity underlying AD.

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

“…For instance, enhanced retention of BACE1 by an ER protein such as RTN/Nogo in the ER can significantly reduce BACE1 cleavage of APP, thereby decreasing Aβ production (Araki et al, 2012; Deng et al, 2013; He et al, 2004; Shi et al, 2014; Shi et al, 2009; Shi et al, 2013; Wojcik et al, 2007). Increased trafficking of BACE1 in the more acidic endosomes by cellular trafficking proteins such as a Vps10p domain-sorting receptor sortilin (Finan et al, 2011), the small GTPase ADP ribosylation factor 6 (ARF6) (Sannerud et al, 2011), Rab-GTPases Rab11 (Udayar et al, 2013), and Sorting nexin 12 (Zhao et al, 2012) results in significant increases in Aβ generation. Golgi-localized γ-ears containing ADP ribosylation factor-binding (GGA) family proteins can bind BACE1 via the di-leucine motif and impact not only its endosomal trafficking, but also its stability (He et al, 2002; He et al, 2005; Santosa et al, 2011; Tesco et al, 2007; von et al, 2015; Wahle et al, 2005; Walker et al, 2012).…”

Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase

“…One possibility is that subcellular location of b-cleavage of APP, which should precede the g-cleavage, is correlated with this difference in the reduction of Ab42 ratio. In fact, recent studies indicate that b-cleavage of APP is dynamically regulated by membrane trafficking [49][50][51] as well as neuronal activity 40,52 .…”

Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein

“…For instance, early endosomes are enlarged in sporadic AD [4, 8], and the levels of proteins involved in endosomal trafficking are altered in AD brains [9]. It has also been shown that perturbation of endosomal proteins can influence APP processing or Aβ production [10, 11]. Moreover, genome-wide association studies (GWAS) have shown that variability in endosomal trafficking genes contributes to the risk of developing AD [12].…”