Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology

J Cell Biol. 2017 Oct 2;216(10):3291-3305. doi: 10.1083/jcb.201612148. Epub 2017 Aug 7.

Abstract

Lysosomes robustly accumulate within axonal swellings at Alzheimer's disease (AD) amyloid plaques. However, the underlying mechanisms and disease relevance of such lysosome accumulations are not well understood. Motivated by these problems, we identified JNK-interacting protein 3 (JIP3) as an important regulator of axonal lysosome transport and maturation. JIP3 knockout mouse neuron primary cultures accumulate lysosomes within focal axonal swellings that resemble the dystrophic axons at amyloid plaques. These swellings contain high levels of amyloid precursor protein processing enzymes (BACE1 and presenilin 2) and are accompanied by elevated Aβ peptide levels. The in vivo importance of the JIP3-dependent regulation of axonal lysosomes was revealed by the worsening of the amyloid plaque pathology arising from JIP3 haploinsufficiency in a mouse model of AD. These results establish the critical role of JIP3-dependent axonal lysosome transport in regulating amyloidogenic amyloid precursor protein processing and support a model wherein Aβ production is amplified by plaque-induced axonal lysosome transport defects.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism
  • Axonal Transport*
  • Axons / metabolism*
  • Axons / pathology
  • Disease Models, Animal
  • Lysosomes / genetics
  • Lysosomes / metabolism*
  • Lysosomes / pathology
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / metabolism*
  • Plaque, Amyloid / pathology
  • Presenilin-2 / genetics
  • Presenilin-2 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • Mapk8ip3 protein, mouse
  • Nerve Tissue Proteins
  • Presenilin-2
  • Psen2 protein, mouse
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse

Associated data

  • GENBANK/BC068312