Dataset Information

Age-Related Intraneuronal Aggregation of Amyloid-? in Endosomes, Mitochondria, Autophagosomes, and Lysosomes.

ABSTRACT: This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iA?), and the mechanism of an age-related increase in iA? in adult AD-model mouse neurons. A new end-specific antibody for A?45 and another for aggregated forms of A? provide new insight into the composition of iA? and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iA? levels containing aggregates of A?45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iA? was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iA? and rapidly increased following a brief metabolic stress with glutamate. A?PP-CTF, A?45, and aggregated A? colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iA? by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long A?s by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iA? processing may lead to application of countermeasures to prolong dementia-free health span.

SUBMITTER: Brewer GJ

PROVIDER: S-EPMC7029321 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes.

Brewer Gregory J GJ Herrera Robert A RA Philipp Stephan S Sosna Justyna J Reyes-Ruiz Jorge Mauricio JM Glabe Charles G CG

Journal of Alzheimer's disease : JAD 20200101 1

This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neuron ...[more]

PMID: 31771065

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Project description: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-? 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-? 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-? aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-? aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-? 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.

Dataset Information

Age-Related Intraneuronal Aggregation of Amyloid-? in Endosomes, Mitochondria, Autophagosomes, and Lysosomes.

Publications

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes.

Similar Datasets

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