Bri2 BRICHOS chaperone rescues impaired fast-spiking interneuron behavior and neuronal network dynamics in an AD mouse model in vitro

Neurobiol Dis. 2021 Nov:159:105514. doi: 10.1016/j.nbd.2021.105514. Epub 2021 Sep 21.

Abstract

Synchronized and properly balanced electrical activity of neurons is the basis for the brain's ability to process information, to learn, and to remember. In Alzheimer's disease (AD), which causes cognitive decline in patients, this synchronization and balance is disturbed by the accumulation of neuropathological biomarkers such as amyloid-beta peptide (Aβ42). Failure of Aβ42 clearance mechanisms as well as desynchronization of crucial neuronal classes such as fast-spiking interneurons (FSN) are root causes for the disruption of the cognition-relevant gamma brain rhythm (30-80 Hz) and consequent cognitive impairment observed in AD. Here we show that recombinant BRICHOS molecular chaperone domains from ProSP-C or Bri2, which interfere with Aβ42 aggregation, can rescue the gamma rhythm. We demonstrate that Aβ42 progressively decreases gamma oscillation power and rhythmicity, disrupts the inhibition/excitation balance in pyramidal cells, and desynchronizes FSN firing during gamma oscillations in the hippocampal CA3 network of mice. Application of the more efficacious Bri2 BRICHOS chaperone rescued the cellular and neuronal network performance from all ongoing Aβ42-induced functional impairments. Collectively, our findings offer critical missing data to explain the importance of FSN for normal network function and underscore the therapeutic potential of Bri2 BRICHOS to rescue the disruption of cognition-relevant brain rhythms in AD.

Keywords: Alzheimer's disease; Bri2 BRICHOS chaperone; Fast-spiking interneurons; Gamma oscillations; hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Action Potentials / physiology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / pharmacology*
  • Amyloid beta-Peptides
  • Animals
  • Disease Models, Animal
  • Gamma Rhythm
  • Hippocampus / drug effects*
  • Hippocampus / physiopathology
  • In Vitro Techniques
  • Interneurons / drug effects*
  • Interneurons / physiology
  • Mice
  • Molecular Chaperones / pharmacology*
  • Neural Pathways / drug effects
  • Neural Pathways / physiopathology
  • Peptide Fragments
  • Protein Domains
  • Pulmonary Surfactant-Associated Protein C / metabolism
  • Pulmonary Surfactant-Associated Protein C / pharmacology
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / physiology
  • Recombinant Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • ITM2B protein, human
  • Molecular Chaperones
  • Peptide Fragments
  • Pulmonary Surfactant-Associated Protein C
  • Recombinant Proteins
  • amyloid beta-protein (1-42)