The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse AD Models

Anaïs Bécot, Raphaëlle Pardossi-Piquard, Alexandre Bourgeois, Eric Duplan, Qingli Xiao, Abhinav Diwan, Jin Moo Lee, Inger Lauritzen

Research output: Contribution to journalArticlepeer-review

Abstract

: Brains that are affected by Alzheimer's disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.

Original languageEnglish
JournalCells
Volume9
Issue number5
DOIs
StatePublished - May 12 2020

Keywords

  • 3xTgAD mice
  • AAV8
  • Alzheimer’s disease
  • C99
  • TFEB
  • cathepsins
  • lysosomes
  • βCTF

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