Cathepsin B Degrades Amyloid-β in Mice Expressing Wild-type Human Amyloid Precursor Protein

Wang, Chao; Sun, Binggui; Zhou, Yungui; Grubb, Anders; Gan, Li

doi:10.1074/jbc.m112.371641

Cited by 94 publications

(113 citation statements)

References 33 publications

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“…Because BACE1 is normally abundantly localized to axons (34) and is degraded by lysosomes (15,38,39), our observations suggest that cathepsin levels might be rate-limiting for the efficient degradation of BACE1 and thus lead to its high abundance at such sites. This concept is supported by previous studies that detected reductions in amyloid plaque burden after the enhancement of cathepsin activity in mouse models of AD (67)(68)(69). Although such studies largely focused on cathepsin-mediated Aβ peptide degradation as a mechanism for explaining the overall reduction in Aβ levels and amyloid plaque load, the possibility that elevated cathepsin levels/activity exerted additional antiamyloidogenic effects via enhanced BACE1 breakdown requires further investigation in light of our new findings.…”

Section: Discussionsupporting

confidence: 58%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

328

326

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Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

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Section: Discussionsupporting

confidence: 58%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

328

326

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“…Among the substrates for CatB is A␤ 42 , which is cleaved in preference to other amyloid-␤ peptide variants, such as A␤ 40 (23). In line with this activity, loss of CatB in gene-targeted mice results in a specific increase in A␤ 42 levels (23) while enhanced CatB activity (caused by gene inactivation of the protease inhibitor cystatin C) lowers A␤ 42 concentrations in the brain (24,25). Impaired functional expression of CI-MPR and its cargo CatB in SY5Y-A/S cells lacking PACS1 (Fig.…”

Section: Discussionmentioning

confidence: 89%

“…Among the enzymes sorted by CI-MPR is CatB, a cysteine protease that degrades peptides in the endosomal-lysosomal system but also in the extracellular space following secretion (22). Because CatB specifically degrades A␤ 42 (23)(24)(25), we reasoned that the SORLA-independent effect of PACS1 knockdown on A␤ 42 levels might work by impacting the CI-MPR-CatB system. This hypothesis was supported when we detected reduced levels of CI-MPR in cell lysates (Fig.…”

Section: Resultsmentioning

confidence: 99%

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

Burgert

Schmidt

Çağlayan

et al. 2013

Molecular and Cellular Biology

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c Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into A␤ peptides, a hallmark of Alzheimer's disease (AD). Several cytosolic adaptors have been shown to interact with the cytoplasmic domain of SORLA, thereby controlling intracellular routing of SORLA/APP complexes in cell lines. However, the relevance of adaptor-mediated sorting of SORLA for amyloidogenic processes in vivo remained unexplored. We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein 1 (PACS1), an adaptor that shuttles proteins between the trans-Golgi network (TGN) and endosomes. By studying PACS1 knockdown in neuronal cell lines and investigating transgenic mice expressing a PACS1-binding-defective mutant form of SORLA, we found that disruption of SORLA and PACS1 interaction results in the inability of SORLA/APP complexes to sort to the TGN in neurons and in increased APP processing in the brain. Loss of PACS1 also impairs the proper expression of the cation-independent mannose 6-phosphate receptor and its target cathepsin B, a protease that breaks down A␤. Thus, our data identified the importance of PACS1-dependent protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms.

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“…Ab accumulates within neuronal lysosomes in AD mice brains and may undergo deposition in the retina by similar mechanisms [95]. Among a wide spectrum of lysosomal enzymes, cathepsins are associated with both production and degradation of Ab directly as well as through activation of other proteases [96]. Cathepsins are well expressed in the retina and are upregulated in AMD and glaucoma conditions [97].…”

Section: Lysosomal and Autophagic Dysregulationmentioning

confidence: 99%

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

Gupta

Chitranshi

et al. 2016

Cell. Mol. Life Sci.

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Accumulation of amyloid β (Aβ) and its aggregates in the ageing central nervous system is regarded synonymous to Alzheimer's disease (AD) pathology. Despite unquestionable advances in mechanistic and diagnostic aspects of the disease understanding, the primary cause of Aβ accumulation as well as its in vivo roles remains elusive; nonetheless, the majority of the efforts to address pathological mechanisms for therapeutic development are focused towards moderating Aβ accumulation in the brain. More recently, Aβ deposition has been identified in the eye and is linked with distinct age-related diseases including age-related macular degeneration, glaucoma as well as AD. Awareness of the Aβ accumulation in these markedly different degenerative disorders has led to an increasing body of work exploring overlapping mechanisms, a prospective biomarker role for Aβ and the potential to use retina as a model for brain related neurodegenerative disorders. Here, we present an integrated view of current understanding of the retinal Aβ deposition discussing the accumulation mechanisms, anticipated impacts and outlining ameliorative approaches that can be extrapolated to the retina for potential therapeutic benefits. Further longitudinal investigations in humans and animal models will determine retinal Aβ association as a potential pathognomonic, diagnostic or prognostic biomarker.

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Cathepsin B Degrades Amyloid-β in Mice Expressing Wild-type Human Amyloid Precursor Protein

Cited by 94 publications

References 33 publications

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

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