Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis

Dun Sheng Yang, Philip Stavrides, Panaiyur S. Mohan, Susmita Kaushik, Asok Kumar, Masuo Ohno, Stephen D. Schmidt, Daniel W. Wesson, Urmi Bandyopadhyay, Ying Jiang, Monika Pawlik, Corrinne M. Peterhoff, Austin J. Yang, Donald A. Wilson, Peter St. George-Hyslop, David Westaway, Paul M. Mathews, Efrat Levy, Ana M. Cuervo, Ralph A. Nixon

Research output: Contribution to journalShort survey

64 Scopus citations

Abstract

The extensive autophagic-lysosomal pathology in Alzheimer disease (AD) brain has revealed a major defect in the proteolytic clearance of autophagy substrates. Autophagy failure contributes on several levels to AD pathogenesis and has become an important therapeutic target for AD and other neurodegenerative diseases. We recently observed broad therapeutic effects of stimulating autophagic-lysosomal proteolysis in the TgCRND8 mouse model of AD that exhibits defective proteolytic clearance of autophagic substrates, robust intralysosomal amyloid-β peptide (Aβ) accumulation, extracellular β-amyloid deposition and cognitive deficits. By genetically deleting the lysosomal cysteine protease inhibitor, cystatin B (CstB), to selectively restore depressed cathepsin activities, we substantially cleared Aβ, ubiquitinated proteins and other autophagic substrates from autolysosomes/lysosomes and rescued autophagic-lysosomal pathology, as well as reduced total Aβ40/42 levels and extracellular amyloid deposition, highlighting the under-appreciated importance of the lysosomal system for Aβ clearance. Most importantly, lysosomal remediation prevented the marked learning and memory deficits in TgCRND8 mice. Our findings underscore the pathogenic significance of autophagic-lysosomal dysfunction in AD and demonstrate the value of reversing this dysfunction as an innovative therapeutic strategy for AD.

Original languageEnglish (US)
Pages (from-to)788-789
Number of pages2
JournalAutophagy
Volume7
Issue number7
DOIs
StatePublished - Jul 2011

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Keywords

  • Alzheimer disease
  • Autophagy
  • Cathepsin
  • Cystatin B
  • Lysosome
  • Proteolysis
  • Transgenic

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Yang, D. S., Stavrides, P., Mohan, P. S., Kaushik, S., Kumar, A., Ohno, M., Schmidt, S. D., Wesson, D. W., Bandyopadhyay, U., Jiang, Y., Pawlik, M., Peterhoff, C. M., Yang, A. J., Wilson, D. A., St. George-Hyslop, P., Westaway, D., Mathews, P. M., Levy, E., Cuervo, A. M., & Nixon, R. A. (2011). Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis. Autophagy, 7(7), 788-789. https://doi.org/10.4161/auto.7.7.15596