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Lysosomal Leakage of Cathepsin B in Alzheimer's Disease and Related Neurodegenerative Brain Disorders

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Abstract

Alzheimer’s disease (AD) is a severe neurodegenerative disease that is becoming one of the major causes of death worldwide. One of the main indicators of AD is neuronal death due to the extracellular accumulation of amyloid-beta (Aβ) plaques, one form being Aβ42 peptide oligomers. Previous studies have shown the involvement of a lysosomal protease called cathepsin B (CatB) and lysosomal leakage, and its implications in cognitive deficits and neuropathology of AD and other related neurodegenerative diseases. These studies show the potential for CatB as a therapeutic target. Here, the extent to which Aβ42 oligomers induce lysosomal leakage and the translocation of CatB is investigated. It is hypothesized that Aβ42 induces lysosomal leakage and the translocation of CatB to the cytosol associated with cell death. Through lactate dehydrogenase (LDH) assays, Aβ42 treatment of SK-N-MC and SH-SY5Y human neuroblastoma cells resulted in cell death cytotoxicity. Fluorescent imaging by acridine orange (AO) staining showed that in both SK-N-MC and SH-SY5Y cells, Aβ42 treatment induced lysosomal leakage. Moreover, western blot analysis of the cytosolic fractions of Aβ42-treated BV2 microglial cells obtained via sucrose density gradient centrifugation showed the presence of pro- and mature CatB. Lastly, using the LES12 bifunctional probe in Aβ42-treated SH-SY5Y cells revealed increased activity of cysteine cathepsins in a cytosolic neutral pH environment. These findings advance the understanding of lysosomal leakage in AD and other related neurodegenerative diseases, demonstrating the new finding that Aβ42 oligomers induce lysosomal leakage of CatB associated with cell death.

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This item is under embargo until September 10, 2023.