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Research Article

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

Swetha Gowrishankar, Peng Yuan, Yumei Wu, Matthew Schrag, Summer Paradise, Jaime Grutzendler, Pietro De Camilli, and Shawn M. Ferguson
  1. aDepartment of Cell Biology,
  2. bProgram in Cellular Neuroscience, Neurodegeneration and Repair,
  3. cHoward Hughes Medical Institute,
  4. dDepartment of Neurology, Yale University School of Medicine, New Haven, CT 06510

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PNAS first published June 29, 2015; https://doi.org/10.1073/pnas.1510329112
Swetha Gowrishankar
aDepartment of Cell Biology,
bProgram in Cellular Neuroscience, Neurodegeneration and Repair,
cHoward Hughes Medical Institute,
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Peng Yuan
bProgram in Cellular Neuroscience, Neurodegeneration and Repair,
dDepartment of Neurology, Yale University School of Medicine, New Haven, CT 06510
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Yumei Wu
aDepartment of Cell Biology,
bProgram in Cellular Neuroscience, Neurodegeneration and Repair,
cHoward Hughes Medical Institute,
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Matthew Schrag
dDepartment of Neurology, Yale University School of Medicine, New Haven, CT 06510
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Summer Paradise
aDepartment of Cell Biology,
bProgram in Cellular Neuroscience, Neurodegeneration and Repair,
cHoward Hughes Medical Institute,
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Jaime Grutzendler
bProgram in Cellular Neuroscience, Neurodegeneration and Repair,
dDepartment of Neurology, Yale University School of Medicine, New Haven, CT 06510
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Pietro De Camilli
aDepartment of Cell Biology,
bProgram in Cellular Neuroscience, Neurodegeneration and Repair,
cHoward Hughes Medical Institute,
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  • For correspondence: shawn.ferguson@yale.edu pietro.decamilli@yale.edu
Shawn M. Ferguson
aDepartment of Cell Biology,
bProgram in Cellular Neuroscience, Neurodegeneration and Repair,
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  • For correspondence: shawn.ferguson@yale.edu pietro.decamilli@yale.edu
  1. Contributed by Pietro De Camilli, May 26, 2015 (sent for review April 29, 2015; reviewed by Thomas Biederer and Joachim Herz)

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Significance

Amyloid plaques, a key feature of Alzheimer’s disease brain pathology, comprise an extracellular β-amyloid core surrounded by tissue enriched in lysosome-like organelles. As a foundation for understanding the mechanisms that drive amyloid plaque formation, we have elucidated the cellular origins and molecular composition of such organelles. The majority of the lysosomes at amyloid plaques reside within swollen neuronal axons. Interestingly, these organelles contain low levels of multiple luminal lysosomal proteases and closely resemble a lysosome subpopulation that naturally occurs in distal neuronal processes. These results suggest that extracellular β-amyloid deposits cause a local impairment in retrograde axonal transport, leading to the accumulation of lysosome precursors and a blockade in their further maturation that has implications for both β-amyloid production and clearance.

Abstract

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.

  • lysosome
  • Alzheimer's
  • progranulin
  • axonal transport
  • cathepsin

Footnotes

  • ↵1To whom correspondence may be addressed. Email: shawn.ferguson{at}yale.edu or pietro.decamilli{at}yale.edu.
  • Author contributions: S.G., P.Y., J.G., P.D.C., and S.M.F. designed research; S.G., P.Y., Y.W., M.S., S.P., and S.M.F. performed research; S.G., P.Y., J.G., P.D.C., and S.M.F. analyzed data; and S.G., P.D.C., and S.M.F. wrote the paper.

  • Reviewers: T.B., Tufts University; and J.H., University of Texas Southwestern.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1510329112/-/DCSupplemental.

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Lysosome accumulations at amyloid plaques
Swetha Gowrishankar, Peng Yuan, Yumei Wu, Matthew Schrag, Summer Paradise, Jaime Grutzendler, Pietro De Camilli, Shawn M. Ferguson
Proceedings of the National Academy of Sciences Jun 2015, 201510329; DOI: 10.1073/pnas.1510329112

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Lysosome accumulations at amyloid plaques
Swetha Gowrishankar, Peng Yuan, Yumei Wu, Matthew Schrag, Summer Paradise, Jaime Grutzendler, Pietro De Camilli, Shawn M. Ferguson
Proceedings of the National Academy of Sciences Jun 2015, 201510329; DOI: 10.1073/pnas.1510329112
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