Deregulated Local Protein Synthesis in the Brain Synaptosomes of a Mouse Model for Alzheimer's Disease

Carolina Cefaliello, Eduardo Penna, Carmela Barbato, Giuseppina Di Ruberto, Maria Pina Mollica, Giovanna Trinchese, Luisa Cigliano, Tiziana Borsello, Jong Tai Chun, Antonio Giuditta, Carla Perrone-Capano, Maria Concetta Miniaci, Marianna Crispino

Research output: Contribution to journalArticlepeer-review

Abstract

While protein synthesis in neurons is largely attributed to cell body and dendrites, the capability of synaptic regions to synthesize new proteins independently of the cell body has been widely demonstrated as an advantageous mechanism subserving synaptic plasticity. Thus, the contribution that local protein synthesis at synapses makes to physiology and pathology of brain plasticity may be more prevalent than initially thought. In this study, we tested if local protein synthesis at synapses is deregulated in the brains of TgCRND8 mice, an animal model for Alzheimer's disease (AD) overexpressing mutant human amyloid precursor protein (APP). To this end, we used synaptosomes as a model system to study the functionality of the synaptic regions in mouse brains. Our results showed that, while TgCRND8 mice exhibit early signs of brain inflammation and deficits in learning, the electrophoretic profile of newly synthesized proteins in their synaptosomes was subtly different from that of the control mice. Interestingly, APP itself was, in part, locally synthesized in the synaptosomes, underscoring the potential importance of local translation at synapses. More importantly, after the contextual fear conditioning, de novo synthesis of some individual proteins was significantly enhanced in the synaptosomes of control animals, but the TgCRND8 mice failed to display such synaptic modulation by training. Taken together, our results demonstrate that synaptic synthesis of proteins is impaired in the brain of a mouse model for AD, and raise the possibility that this deregulation may contribute to the early progression of the pathology.

Original languageEnglish
Pages (from-to)1529-1541
Number of pages13
JournalMolecular Neurobiology
Volume57
Issue number3
DOIs
Publication statusPublished - Mar 2020

Keywords

  • Alzheimer Disease/metabolism
  • Amyloid beta-Peptides/metabolism
  • Amyloid beta-Protein Precursor/metabolism
  • Animals
  • Brain/metabolism
  • Disease Models, Animal
  • Memory Disorders/metabolism
  • Mice, Transgenic
  • Neurons/metabolism
  • Plaque, Amyloid/pathology
  • Synapses/metabolism
  • Synaptosomes/metabolism

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