Autophagy-related protein 7 deficiency in amyloid β (Aβ) precursor protein transgenic mice decreases Aβ in the multivesicular bodies and induces Aβ accumulation in the Golgi

Am J Pathol. 2015 Feb;185(2):305-13. doi: 10.1016/j.ajpath.2014.10.011. Epub 2014 Nov 26.

Abstract

Alzheimer disease (AD) is biochemically characterized by increased levels of amyloid β (Aβ) peptide, which aggregates into extracellular Aβ plaques in AD brains. Before plaque formation, Aβ accumulates intracellularly in both AD brains and in the brains of AD model mice, which may contribute to disease progression. Autophagy, which is impaired in AD, clears cellular protein aggregates and participates in Aβ metabolism. In addition to a degradative role of autophagy in Aβ metabolism we recently showed that Aβ secretion is inhibited in mice lacking autophagy-related gene 7 (Atg7) in excitatory neurons in the mouse forebrain. This inhibition of Aβ secretion leads to intracellular accumulation of Aβ. Here, we used fluorescence and immunoelectron microscopy to elucidate the subcellular localization of the intracellular Aβ accumulation which accumulates in Aβ precursor protein mice lacking Atg7. Autophagy deficiency causes accumulation of p62(+) aggregates, but these aggregates do not contain Aβ. However, knockdown of Atg7 induced Aβ accumulation in the Golgi and a concomitant reduction of Aβ in the multivesicular bodies. This indicates that Atg7 influences the transport of Aβ possibly derived from Golgi to multivesicular bodies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Autophagy-Related Protein 7
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism*
  • Golgi Apparatus / pathology
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / deficiency*
  • Microtubule-Associated Proteins / metabolism
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Protein Aggregates*

Substances

  • Amyloid beta-Peptides
  • Atg7 protein, mouse
  • Microtubule-Associated Proteins
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-40)
  • Autophagy-Related Protein 7