Dysregulation of Rab5-mediated endocytic pathways in Alzheimer's disease

Abstract

Increasing evidence has pointed to that dysregulation of the endo-lysosomal system is an early cellular phenotype of pathogenesis for Alzheimer's disease (AD). Rab5, a small GTPase, plays a critical role in mediating these processes. Abnormal overactivation of Rab5 has been observed in post-mortem brain samples of Alzheimer's patients as well as brain samples of mouse models of AD. Recent genome-wide association studies of AD have identified RIN3 (Ras and Rab interactor 3) as a novel risk factor for the disease. RIN3 that functions as a guanine nucleotide exchange factor for Rab5 may serve as an important activator for Rab5 in AD pathogenesis. In this review, we present recent research highlights on the possible roles of dysregulation of Rab5-mediated endocytic pathways in contributing to early pathogenesis of AD.

Keywords: Alzheimer's disease; Rab5; atrophy; axonal dysfunction; axonal transport; endocytosis; neurodegeneration.

Figure 1

A simplified depiction of an NGF signaling endosome showing that NGF binds to TrkA that activates the Erk, PI3K and PLCγ signaling cascades. In addition, APP/APP βCTF may act through RIN3 or APPL1 to activate Rab5. The dynein motor protein complex is also required to drive the retrograde axonal transport of the NGF signaling endosome.

Figure 2

Proposed models for retrograde axonal transport function of NGF signaling endosomes in normal neurons (A) and under conditions of excess APP or APP βCTF (B). Please see the text for a detailed description.

Figure 3

Domain structures of RIN3 (A) and APPL1 (B). A: RIN3 is consisted of a SH2 domain (a Src homology 2 domain), a proline rich domain (PRD), a RIN-homology domain (RH), a Vsp9 domain [vacuolar protein sorting-associated protein 9 domain that is conserved in the catalytic domains of the Rab5 GEFs (Vps9p, Rabex-5 etc.)], and a Ras-association domain (RA)^,. B: APPLI contains a BAR (Bin/Amphiphysin/Rvs) domain, a PH (pleckstrin homology) domain and a PTB (phosphotyrosine-binding) domain.