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

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 underappreciated 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 therapeautic strategy for AD.

journal_name

Autophagy

journal_title

Autophagy

authors

Yang DS,Stavrides P,Mohan PS,Kaushik S,Kumar A,Ohno M,Schmidt SD,Wesson DW,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

doi

10.4161/auto.7.7.15596

subject

Has Abstract

pub_date

2011-07-01 00:00:00

pages

788-9

issue

7

eissn

1554-8627

issn

1554-8635

pii

15596

journal_volume

7

pub_type

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