Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits

Dun Sheng Yang, Philip Stavrides, Panaiyur S. Mohan, Susmita Kaushik, Asok Kumar, Masuo Ohno, Stephen D. Schmidt, Daniel 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 Maria Cuervo, Ralph A. Nixon

Research output: Contribution to journalArticle

271 Citations (Scopus)

Abstract

Autophagy, a major degradative pathway for proteins and organelles, is essential for survival of mature neurons. Extensive autophagic-lysosomal pathology in Alzheimer's disease brain contributes to Alzheimer's disease pathogenesis, although the underlying mechanisms are not well understood. Here, we identified and characterized marked intraneuronal amyloid-β peptide/amyloid and lysosomal system pathology in the Alzheimer's disease mouse model TgCRND8 similar to that previously described in Alzheimer's disease brains. We further establish that the basis for these pathologies involves defective proteolytic clearance of neuronal autophagic substrates including amyloid-β peptide. To establish the pathogenic significance of these abnormalities, we enhanced lysosomal cathepsin activities and rates of autophagic protein turnover in TgCRND8 mice by genetically deleting cystatin B, an endogenous inhibitor of lysosomal cysteine proteases. Cystatin B deletion rescued autophagic-lysosomal pathology, reduced abnormal accumulations of amyloid-β peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-β peptide. The amelioration of lysosomal function in TgCRND8 markedly decreased extracellular amyloid deposition and total brain amyloid-β peptide 40 and 42 levels, and prevented the development of deficits of learning and memory in fear conditioning and olfactory habituation tests. Our findings support the pathogenic significance of autophagic-lysosomal dysfunction in Alzheimer's disease and indicate the potential value of restoring normal autophagy as an innovative therapeutic strategy for Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)258-277
Number of pages20
JournalBrain
Volume134
Issue number1
DOIs
StatePublished - Jan 2011

Fingerprint

Autophagy
Memory Disorders
Amyloid
Alzheimer Disease
Pathology
Cystatin B
Peptides
Brain
Ubiquitinated Proteins
Cysteine Proteinase Inhibitors
Cathepsins
Lysosomes
Organelles
Fear
Reference Values
Proteins
Learning
Neurons

Keywords

  • Alzheimer's disease
  • autophagy
  • cathepsin
  • cystatin B
  • lysosome

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. / Yang, Dun Sheng; Stavrides, Philip; Mohan, Panaiyur S.; Kaushik, Susmita; Kumar, Asok; Ohno, Masuo; Schmidt, Stephen D.; Wesson, Daniel; Bandyopadhyay, Urmi; Jiang, Ying; Pawlik, Monika; Peterhoff, Corrinne M.; Yang, Austin J.; Wilson, Donald A.; St George-Hyslop, Peter; Westaway, David; Mathews, Paul M.; Levy, Efrat; Cuervo, Ana Maria; Nixon, Ralph A.

In: Brain, Vol. 134, No. 1, 01.2011, p. 258-277.

Research output: Contribution to journalArticle

Yang, DS, Stavrides, P, Mohan, PS, Kaushik, S, Kumar, A, Ohno, M, Schmidt, SD, Wesson, D, Bandyopadhyay, U, Jiang, Y, Pawlik, M, Peterhoff, CM, Yang, AJ, Wilson, DA, St George-Hyslop, P, Westaway, D, Mathews, PM, Levy, E, Cuervo, AM & Nixon, RA 2011, 'Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits', Brain, vol. 134, no. 1, pp. 258-277. https://doi.org/10.1093/brain/awq341
Yang, Dun Sheng ; Stavrides, Philip ; Mohan, Panaiyur S. ; Kaushik, Susmita ; Kumar, Asok ; Ohno, Masuo ; Schmidt, Stephen D. ; Wesson, Daniel ; Bandyopadhyay, Urmi ; Jiang, Ying ; Pawlik, Monika ; Peterhoff, Corrinne M. ; Yang, Austin J. ; Wilson, Donald A. ; St George-Hyslop, Peter ; Westaway, David ; Mathews, Paul M. ; Levy, Efrat ; Cuervo, Ana Maria ; Nixon, Ralph A. / Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. In: Brain. 2011 ; Vol. 134, No. 1. pp. 258-277.
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abstract = "Autophagy, a major degradative pathway for proteins and organelles, is essential for survival of mature neurons. Extensive autophagic-lysosomal pathology in Alzheimer's disease brain contributes to Alzheimer's disease pathogenesis, although the underlying mechanisms are not well understood. Here, we identified and characterized marked intraneuronal amyloid-β peptide/amyloid and lysosomal system pathology in the Alzheimer's disease mouse model TgCRND8 similar to that previously described in Alzheimer's disease brains. We further establish that the basis for these pathologies involves defective proteolytic clearance of neuronal autophagic substrates including amyloid-β peptide. To establish the pathogenic significance of these abnormalities, we enhanced lysosomal cathepsin activities and rates of autophagic protein turnover in TgCRND8 mice by genetically deleting cystatin B, an endogenous inhibitor of lysosomal cysteine proteases. Cystatin B deletion rescued autophagic-lysosomal pathology, reduced abnormal accumulations of amyloid-β peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-β peptide. The amelioration of lysosomal function in TgCRND8 markedly decreased extracellular amyloid deposition and total brain amyloid-β peptide 40 and 42 levels, and prevented the development of deficits of learning and memory in fear conditioning and olfactory habituation tests. Our findings support the pathogenic significance of autophagic-lysosomal dysfunction in Alzheimer's disease and indicate the potential value of restoring normal autophagy as an innovative therapeutic strategy for Alzheimer's disease.",
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AU - Yang, Dun Sheng

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AU - Kaushik, Susmita

AU - Kumar, Asok

AU - Ohno, Masuo

AU - Schmidt, Stephen D.

AU - Wesson, Daniel

AU - Bandyopadhyay, Urmi

AU - Jiang, Ying

AU - Pawlik, Monika

AU - Peterhoff, Corrinne M.

AU - Yang, Austin J.

AU - Wilson, Donald A.

AU - St George-Hyslop, Peter

AU - Westaway, David

AU - Mathews, Paul M.

AU - Levy, Efrat

AU - Cuervo, Ana Maria

AU - Nixon, Ralph A.

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N2 - Autophagy, a major degradative pathway for proteins and organelles, is essential for survival of mature neurons. Extensive autophagic-lysosomal pathology in Alzheimer's disease brain contributes to Alzheimer's disease pathogenesis, although the underlying mechanisms are not well understood. Here, we identified and characterized marked intraneuronal amyloid-β peptide/amyloid and lysosomal system pathology in the Alzheimer's disease mouse model TgCRND8 similar to that previously described in Alzheimer's disease brains. We further establish that the basis for these pathologies involves defective proteolytic clearance of neuronal autophagic substrates including amyloid-β peptide. To establish the pathogenic significance of these abnormalities, we enhanced lysosomal cathepsin activities and rates of autophagic protein turnover in TgCRND8 mice by genetically deleting cystatin B, an endogenous inhibitor of lysosomal cysteine proteases. Cystatin B deletion rescued autophagic-lysosomal pathology, reduced abnormal accumulations of amyloid-β peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-β peptide. The amelioration of lysosomal function in TgCRND8 markedly decreased extracellular amyloid deposition and total brain amyloid-β peptide 40 and 42 levels, and prevented the development of deficits of learning and memory in fear conditioning and olfactory habituation tests. Our findings support the pathogenic significance of autophagic-lysosomal dysfunction in Alzheimer's disease and indicate the potential value of restoring normal autophagy as an innovative therapeutic strategy for Alzheimer's disease.

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