Aß42-mediated proteasome inhibition and associated tau pathology in hippocampus are governed by a lysosomal response involving cathepsin B: Evidence for protective crosstalk between protein clearance pathways

UNCP Author/Contributor (non-UNCP co-authors, if there are any, appear on document)
Dr . Ben Bahr, William C. Friday Chair and Professor of Molecular Biology and Biochemistry (Creator)
Dr. Karen Farizatto, Postdoctoral Fellow (Creator)
Institution
The University of North Carolina at Pembroke (UNCP )
Web Site: http://www.uncp.edu/academics/library

Abstract: Impaired protein clearance likely increases the risk of protein accumulation disorders including Alzheimer’s disease (AD). Protein degradation through the proteasome pathway decreases with age and in AD brains, and the Aß42 peptide has been shown to impair proteasome function in cultured cells and in a cell-free model. Here, Aß42 was studied in brain tissue to measure changes in protein clearance pathways and related secondary pathology. Oligomerized Aß42 (0.5–1.5 µM) reduced proteasome activity by 62% in hippocampal slice cultures over a 4-6-day period, corresponding with increased tau phosphorylation and reduced synaptophysin levels. Interestingly, the decrease in proteasome activity was associated with a delayed inverse effect, >2-fold increase, regarding lysosomal cathepsin B (CatB) activity. The CatB enhancement did not correspond with the Aß42-mediated phospho-tau alterations since the latter occurred prior to the CatB response. Hippocampal slices treated with the proteasome inhibitor lactacystin also exhibited an inverse effect on CatB activity with respect to diminished proteasome function. Lactacystin caused earlier CatB enhancement than Aß42, and no correspondence was evident between up-regulated CatB levels and the delayed synaptic pathology indicated by the loss of pre- and postsynaptic markers. Contrasting the inverse effects on the proteasomal and lysosomal pathways by Aß42 and lactacystin, such were not found when CatB activity was up-regulated two-fold with Z-Phe-Ala-diazomethylketone (PADK). Instead of an inverse decline, proteasome function was increased marginally in PADK-treated hippocampal slices. Unexpectedly, the proteasomal augmentation was significantly pronounced in Aß42-compromised slices, while absent in lactacystin-treated tissue, resulting in >2-fold improvement for nearly complete recovery of proteasome function by the CatB-enhancing compound. The PADK treatment also reduced Aß42-mediated tau phosphorylation and synaptic marker declines, corresponding with the positive modulation of both proteasome activity and the lysosomal CatB enzyme. These findings indicate that proteasomal stress contributes to AD-type pathogenesis and that governing such pathology occurs through crosstalk between the two protein clearance pathways.

Additional Information

Publication
PLOS One Vol 12, No. 8
Language: English
Date: 2017
Keywords
Alzheimer's disease, Aß42, Aß42-mediated proteasome,proteasome, inhibitor, tau pathology, cathepsin B, protein pathways, hippocampus

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