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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

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

De Kimpe Line L van Haastert Elise S ES Kaminari Archontia A Zwart Rob R Rutjes Helma H Hoozemans Jeroen J M JJ Scheper Wiep W

Age (Dordrecht, Netherlands) 20120404 3

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 p ...[more]

PMID: 22477259

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Project description:Cerebrovascular pathology often co-exists with Alzheimer's disease pathology and can contribute to Alzheimer's disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer's disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-β pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-β pathology. All underwent baseline tau-PET (18F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0 years. Tau-PET uptake was computed for a temporal meta-region-of-interest. We focused on four main vascular imaging features and risk factors: microbleeds; white matter lesion volume; stroke-related events (infarcts, lacunes and haemorrhages); and the Framingham Heart Study Cardiovascular Disease risk score. To validate our in vivo results, we examined 1610 autopsy cases from an Arizona-based neuropathology cohort on three main vascular pathological features: cerebral amyloid angiopathy; white matter rarefaction; and infarcts. For the in vivo cohort, primary analyses included age-, sex- and APOE ɛ4-corrected linear mixed models between tau-PET (outcome) and interactions between time, amyloid-β and each vascular feature (predictors). For the neuropathology cohort, age-, sex- and APOE ɛ4-corrected linear models between tau tangle density (outcome) and an interaction between plaque density and each vascular feature (predictors) were performed. In cognitively unimpaired individuals, we observed a significant interaction between microbleeds and amyloid-β pathology on greater baseline tau load (β = 0.68, P < 0.001) and longitudinal tau accumulation (β = 0.11, P < 0.001). For white matter lesion volume, we did not observe a significant independent interaction effect with amyloid-β on tau after accounting for microbleeds. In cognitively unimpaired individuals, we further found that stroke-related events showed a significant negative interaction with amyloid-β on longitudinal tau (β = -0.08, P < 0.001). In cognitively impaired individuals, there were no significant interaction effects between cerebrovascular and amyloid-β pathology at all. In the neuropathology dataset, the in vivo observed interaction effects between cerebral amyloid angiopathy and plaque density (β = 0.38, P < 0.001) and between infarcts and plaque density (β = -0.11, P = 0.005) on tau tangle density were replicated. To conclude, we demonstrated that cerebrovascular pathology-in the presence of amyloid-β pathology-modifies tau accumulation in early stages of Alzheimer's disease. More specifically, the co-occurrence of microbleeds and amyloid-β pathology was associated with greater accumulation of tau aggregates during early disease stages. This opens the possibility that interventions targeting microbleeds may attenuate the rate of tau accumulation in Alzheimer's disease.

Dataset Information

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

Publications

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

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