Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer's disease neurons.

Prasad Tammineni,Qian Cai,Daniyal Aikal,Xuan Ye,Tuancheng Feng

doi:10.7554/elife.21776

Abstract

Neurons face unique challenges of transporting nascent autophagic vacuoles (AVs) from distal axons toward the soma, where mature lysosomes are mainly located. Autophagy defects have been linked to Alzheimer's disease (AD). However, the mechanisms underlying altered autophagy remain unknown. Here, we demonstrate that defective retrograde transport contributes to autophagic stress in AD axons. Amphisomes predominantly accumulate at axonal terminals of mutant hAPP mice and AD patient brains. Amyloid-β (Aβ) oligomers associate with AVs in AD axons and interact with dynein motors. This interaction impairs dynein recruitment to amphisomes through competitive interruption of dynein-Snapin motor-adaptor coupling, thus immobilizing them in distal axons. Consistently, deletion of Snapin in mice causes AD-like axonal autophagic stress, whereas overexpressing Snapin in hAPP neurons reduces autophagic accumulation at presynaptic terminals by enhancing AV retrograde transport. Altogether, our study provides new mechanistic insight into AD-associated autophagic stress, thus establishing a foundation for ameliorating axonal pathology in AD.

Highlights

Autophagy is the major cellular degradation pathway for long-lived proteins and organelles (Nixon, 2013; Rubinsztein et al, 2011; Schneider and Cuervo, 2014; Yue et al, 2009)
Autophagic accumulation in the distal axons of mutant hAPP Tg mouse brains To determine whether autophagy is altered in Alzheimer’s disease (AD) neurons, we first examined the hippocampi of both wild-type (WT) and hAPP transgenic (Tg) mice harboring the human AD Swedish and Indiana mutations (Camk2a-tTA X tet-APPswe/ind) (Jankowsky et al, 2005)
While 21.05% of LC3-marked autophagic vacuoles (AVs) localized to MAP2-labeled dendrites, 83.11% and 91.64% of AVs co-localized with the presynaptic marker synaptophysin and along Neurofilament (NF)-labeled axons, suggesting that autophagic stress occurs predominantly in the axons and presynaptic terminals of AD mouse brains (Figure 1—figure supplement 1A,B)

Summary

Introduction

Autophagy is the major cellular degradation pathway for long-lived proteins and organelles (Nixon, 2013; Rubinsztein et al, 2011; Schneider and Cuervo, 2014; Yue et al, 2009). Ultrastructural analysis revealed that AD brains display a unique autophagic stress phenotype: autophagic vacuoles (AVs) massively accumulate and cluster within large swellings along dystrophic neurites (Nixon et al, 2005), a typical amyloid b (Ab)-associated phenotype not found in other neurodegenerative diseases (Benzing et al, 1993). The mechanisms underlying such autophagic stress in AD neurons are largely unknown. Such retrograde transport is initiated by fusion of nascent autophagosomes with late endosomes (LEs) into

Methods

Results

Conclusion