Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation.

Nicole Groh,Anika Bühler,Ka Wan Li,Chaolie Huang,Pim Van Nierop,Frank Baumann,Della C David,August B Smit,Marcus Fändrich

doi:10.3389/fnagi.2017.00138

Abstract

Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer’s disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-β plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-β aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-β aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-β aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-β plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.

Highlights

A variety of neurodegenerative diseases are associated with the misfolding and aggregation of specific proteins
We first investigated whether age-dependent protein aggregates formed during aging in C. elegans have the potential to seed the aggregation of synthetic Aβ in vitro
C. elegans has been extensively characterized as a model for aging (Antebi, 2007) and widespread protein aggregation with age has been repeatedly documented (David et al, 2010; ReisRodrigues et al, 2012; Walther et al, 2015)

Summary

Introduction

A variety of neurodegenerative diseases are associated with the misfolding and aggregation of specific proteins. In recent years, understanding the initiation and spread of these hallmark protein aggregates has become a central area of Heterologous Seeding of Amyloid-β investigation (Jucker and Walker, 2011). The current model stipulates that aggregation in disease is initiated by a protein seed that forms a template for further protein aggregation (Jucker and Walker, 2013). Support for this model comes from research showing that the exogenous addition of minute amounts of Aβ or tau seeds greatly accelerates the onset of aggregation both in vitro and in vivo (Clavaguera et al, 2009; Langer et al, 2011; Nagarathinam et al, 2013). Numerous publications demonstrate that protein aggregation is not restricted to disease but a normal consequence and possibly cause of aging (David et al, 2010; Demontis and Perrimon, 2010; Peters et al, 2012; Reis-Rodrigues et al, 2012; Ottis et al, 2013; Walther et al, 2015; Ayyadevara et al, 2016b; Tanase et al, 2016; Lechler et al, 2017)

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