Negative Regulation of Cathepsins by β-Amyloid

Overview

Journal eNeuro

Specialty Neurology

Date 2024 Jan 10

PMID 38199815

Authors

Brianna Lundin

Anne-Claire Comby

Oksana Berezovska

Masato Maesako

Affiliations

Soon will be listed here.

Abstract

Genome wide association study (GWAS) uncovered Alzheimer's disease (AD) risk genes linked to the endo-lysosomal pathway. This pathway seems to be the gateway of protein aggregates, such as tau and α-synuclein, to the cytoplasm. Furthermore, we and others reported that the amyloid precursor protein (APP) C99 is predominantly processed by γ-secretase in the endo-lysosomal compartments, and β-amyloid (Aβ) peptides are enriched in the same subcellular loci. While the role(s) of APP/Aβ in the endo-lysosomal pathway has not been fully established, a recent study reported that Aβ, in particular Aβ42, inhibits cathepsin D (CTSD) activity. Here, we show using a cell-free in vitro assay that Aβ42 also blocks cathepsin B (CTSB) activity. Furthermore, we uncovered that the autocatalytic processing (i.e., conversion of single chain to heavy/light chains) of CTSB and CTSD is accelerated in APP-deficient cells compared with wild-type controls. Taken together, our findings further support the negative regulation of cathepsins by Aβ.

Citing Articles

Blood Cathepsins on the Risk of Alzheimer's Disease and Related Pathological Biomarkers: Results from Observational Cohort and Mendelian Randomization Study.

Qian X, Ding G, Chen S, Liu X, Zhang M, Tang H J Prev Alzheimers Dis. 2024; 11(6):1834-1842.

PMID: 39559895 PMC: 11573867. DOI: 10.14283/jpad.2024.107.

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