Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation

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.

Spermine increases acetylation of tubulins and facilitates autophagic degradation of prion aggregates

“…We and others have reported impaired autophagy pathway in aging cells 47 , 48 and it has been shown that the aging brain can trigger the formation of amyloid aggregates though the mechanisms remain unknown 49 . Massive accumulation of autophagic vacuoles within large swellings along dystrophic and degenerating neurites is common in AD and other protein misfolding diseases and this could be related to defects in various steps of the autophagy pathway such as initiation of autophagosome formation 50 , 51 , cargo recognition 52 , autophagosome-lysosome fusion 53 , 54 , lysosomal proteolysis 55 , 56 as well as a defect in retrograde transport responsible for the trafficking of cargo filled autophagosomes from the cellular periphery to the lysosomes residing near the nuclear core 57 .…”

Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans

“…Therefore, age-dependent aggregation-prone proteins interact with disease-aggregating proteins in humans. Furthermore, we have demonstrated that minute amounts of insoluble proteins from aged wild-type mouse brains or aged C. elegans is sufficient to cross-seed amyloid-β aggregation in vitro (17). One possibility is that the highly hydrophobic nature of the amyloid-like structures in age-dependent protein aggregates provides a destabilizing surface that can promote the conformational conversion of disease-associated aggregating proteins.…”

“…Since the initial discovery in C. elegans, age-dependent protein aggregation has been demonstrated in different organs in mammals (14)(15)(16)(17)(18). Importantly, age-dependent protein aggregation is likely to be relevant in neurodegenerative processes.…”

“…Indeed, the over-representation of proteins prone to aggregate with age among proteins sequestered in Alzheimer's disease inclusions of amyloid plaques and tau neurofibrillary tangles highlights a possible contribution to pathological processes (12). Moreover, recent evidence shows that aggregates from wild-type aged mouse brains are a potent heterologous seed for amyloid-β (Aβ) aggregation (17). However, because of the difficulties to distinguish the effects of protein aggregation from other consequences of aging, it is still not clear whether age-dependent protein aggregation plays a role in accelerating the aging process (19).…”

Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency

“…We focused on this apparent dysregulation of protein homeostasis in A-T cells because many of the more common neurodegenerative diseases in the human population are associated with aggregation of specific polypeptides in the brain, in some cases with clear causative links between the aggregation and neurotoxicity, and diverse model systems have confirmed these relationships (Bourdenx et al, 2017;Currais et al, 2017;Gidalevitz et al, 2006;Groh et al, 2017; Kikis et al, 2010;Ross and Poirier, 2004). In addition, several of the SCA ataxias, while associated with diverse genetic mutations, generate aggregation-prone mutant proteins that cause cerebellum-specific neurodegeneration similar to that observed in A-T (Buijsen et al, 2019;Klockgether et al, 2019).…”