Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome

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