Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals

Timothy J. Hark, Nalini R. Rao, Charlotte Castillon, Tamara Basta, Samuel Smukowski, Huan Bao, Arun Upadhyay, Ewa Bomba-Warczak, Toshihiro Nomura, Eileen T. O'Toole, Garry P. Morgan, Laith Ali, Takashi Saito, Christelle Guillermier, Takaomi C. Saido, Matthew L. Steinhauser, Michael H.B. Stowell, Edwin R. Chapman, Anis Contractor, Jeffrey N. Savas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Hark et al. use dynamic metabolic 15N labeling and mass-spectrometry-based proteomics to investigate changes to protein turnover in App knockin mice. In this preclinical Alzheimer's disease mouse model, they find that proteostasis in the presynaptic terminal is specifically altered. Synaptic vesicle (SV)-associated proteins functioning in exo- and endocytosis have impaired degradation and elevated levels in the cortex and hippocampus. Finally, the readily releasable SV pool and presynaptic potentiation is enhanced at the earliest stages of amyloid beta accumulation.

Original languageEnglish (US)
Pages (from-to)141-158.e9
JournalCell Systems
Volume12
Issue number2
DOIs
StatePublished - Feb 17 2021

Keywords

  • APP knockin mice
  • Alzheimer's disease
  • amyloid beta
  • mass spectrometry
  • presynapse
  • proteomics
  • proteostasis
  • synaptic dysfunction
  • synaptic vesicles

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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