Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and A? pathology at the lysosome.

ABSTRACT: Deposition of aggregated amyloid beta (A?) is a major hallmark of Alzheimer's disease (AD)-a common age-related neurodegenerative disorder. Typically, A? is generated as a peptide of varying lengths. However, a major fraction of A? peptides in the brains of AD patients has undergone posttranslational modifications, which often radically change the properties of the peptides. A?3(pE)-42 is an N-truncated, pyroglutamate-modified variant that is abundantly present in AD brain and was suggested to play a role early in the pathogenesis. Here we show that intracellular accumulation of oligomeric aggregates of A?3(pE)-42 results in loss of lysosomal integrity. Using a novel antibody specific for aggregates of A?pE3, we show that in postmortem human brain tissue, aggregated A?pE3 is predominantly found in the lysosomes of both neurons and glial cells. Our data further demonstrate that A?pE3 is relatively resistant to lysosomal degradation, which may explain its accumulation in the lysosomes. The intracellular A?pE3 aggregates increase in an age-dependent manner. The results presented in this study support a model where A? pathology and aging converge, leading to accumulation of the degradation-resistant pE-modified A? in the lysosomes, lysosomal dysfunction, and neurodegeneration.

SUBMITTER: De Kimpe L 

PROVIDER: S-EPMC3636379 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature