Cathepsin B abundance, activity and microglial localisation in Alzheimer's disease-Down syndrome and early onset Alzheimer's disease; the role of elevated cystatin B.

Autor: Wu Y; The UK Dementia Research Institute, University College London, Queen Square, London, WC1N 3BG, UK., Mumford P; The UK Dementia Research Institute, University College London, Queen Square, London, WC1N 3BG, UK., Noy S; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK., Cleverley K; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK., Mrzyglod A; The UK Dementia Research Institute, University College London, Queen Square, London, WC1N 3BG, UK., Luo D; The UK Dementia Research Institute, University College London, Queen Square, London, WC1N 3BG, UK., van Dalen F; Department of Medical BioSciences, Radboudumc, Geert Grooteplein Zuid 28, 6525 GA, Nijmegen, The Netherlands.; Institute for Chemical Immunology, Geert Grooteplein Zuid 28, 6525 GA, Nijmegen, The Netherlands., Verdoes M; Department of Medical BioSciences, Radboudumc, Geert Grooteplein Zuid 28, 6525 GA, Nijmegen, The Netherlands.; Institute for Chemical Immunology, Geert Grooteplein Zuid 28, 6525 GA, Nijmegen, The Netherlands., Fisher EMC; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK., Wiseman FK; The UK Dementia Research Institute, University College London, Queen Square, London, WC1N 3BG, UK. f.wiseman@ucl.ac.uk.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2023 Aug 14; Vol. 11 (1), pp. 132. Date of Electronic Publication: 2023 Aug 14.
DOI: 10.1186/s40478-023-01632-8
Abstrakt: Cathepsin B is a cysteine protease that is implicated in multiple aspects of Alzheimer's disease pathogenesis. The endogenous inhibitor of this enzyme, cystatin B (CSTB) is encoded on chromosome 21. Thus, individuals who have Down syndrome, a genetic condition caused by having an additional copy of chromosome 21, have an extra copy of an endogenous inhibitor of the enzyme. Individuals who have Down syndrome are also at significantly increased risk of developing early-onset Alzheimer's disease (EOAD). The impact of the additional copy of CSTB on Alzheimer's disease development in people who have Down syndrome is not well understood. Here we compared the biology of cathepsin B and CSTB in individuals who had Down syndrome and Alzheimer's disease, with disomic individuals who had Alzheimer's disease or were ageing healthily. We find that the activity of cathepsin B enzyme is decreased in the brain of people who had Down syndrome and Alzheimer's disease compared with disomic individuals who had Alzheimer's disease. This change occurs independently of an alteration in the abundance of the mature enzyme or the number of cathepsin B + cells. We find that the abundance of CSTB is significantly increased in the brains of individuals who have Down syndrome and Alzheimer's disease compared to disomic individuals both with and without Alzheimer's disease. In mouse and human cellular preclinical models of Down syndrome, three-copies of CSTB increases CSTB protein abundance but this is not sufficient to modulate cathepsin B activity. EOAD and Alzheimer's disease-Down syndrome share many overlapping mechanisms but differences in disease occur in individuals who have trisomy 21. Understanding this biology will ensure that people who have Down syndrome access the most appropriate Alzheimer's disease therapeutics and moreover will provide unique insight into disease pathogenesis more broadly.
(© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze: MEDLINE
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