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

Line De Kimpe,Archontia Kaminari,Elise S Van Haastert,Wiep Scheper,Jeroen J M Hoozemans,Rob Zwart,Helma Rutjes

doi:10.1007/s11357-012-9403-0

Abstract

Deposition of aggregated amyloid beta (Aβ) is a major hallmark of Alzheimer’s disease (AD)—a common age-related neurodegenerative disorder. Typically, Aβ is generated as a peptide of varying lengths. However, a major fraction of Aβ peptides in the brains of AD patients has undergone posttranslational modifications, which often radically change the properties of the peptides. Aβ3(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 Aβ3(pE)-42 results in loss of lysosomal integrity. Using a novel antibody specific for aggregates of AβpE3, we show that in postmortem human brain tissue, aggregated AβpE3 is predominantly found in the lysosomes of both neurons and glial cells. Our data further demonstrate that AβpE3 is relatively resistant to lysosomal degradation, which may explain its accumulation in the lysosomes. The intracellular AβpE3 aggregates increase in an age-dependent manner. The results presented in this study support a model where Aβ pathology and aging converge, leading to accumulation of the degradation-resistant pE-modified Aβ in the lysosomes, lysosomal dysfunction, and neurodegeneration.Electronic supplementary materialThe online version of this article (doi:10.1007/s11357-012-9403-0) contains supplementary material, which is available to authorized users.

Highlights

Alzheimer’s disease (AD) is a common progressive neurodegenerative disorder of which the prevalence is steeply increasing in the aging society
Inhibition of uptake of oligomeric Aβ1-42 decreases toxicity (Chafekar et al 2008) suggesting that the lysosome is involved in Aβ toxicity
Differentiated SK-N-SH cells were treated with Aβ oligomers and the leakage of cathepsin D (CTD), a soluble lysosomal enzyme, from the lysosomal lumen to the cytosol was analyzed after subcellular fractionation on Western blot and by immunofluorescent staining

Summary

Introduction

Alzheimer’s disease (AD) is a common progressive neurodegenerative disorder of which the prevalence is steeply increasing in the aging society. AD is characterized by deposits of aggregated proteins: intracellular aggregates of hyperphosphorylated tau in neurofibrillary tangles and extracellular β-amyloid (Aβ) in plaques. According to the widely supported amyloid cascade hypothesis, increased levels and the formation of assemblies of Aβ is one of earliest events in AD pathogenesis (Hardy and Selkoe 2002). Aβ is prone to self-aggregate and the formation of the resulting aggregates is strongly linked to the development of the disease. Despite enormous research efforts, the exact site and mechanism of Aβ toxicity is still not entirely elucidated. A major obstacle in Aβ research is that Aβ is not a single entity but a peptide with great molecular heterogeneity (De Kimpe and Scheper 2010)

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Results

Conclusion