14-3-3θ Does Not Protect against Behavioral or Pathological Deficits in Alzheimer's Disease Mouse Models

eNeuro. 2022 Jun 24;9(3):ENEURO.0368-21.2022. doi: 10.1523/ENEURO.0368-21.2022. Print 2022 May-Jun.

Abstract

Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with synaptic dysfunction and dendritic spine loss and the pathologic hallmarks of β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles. 14-3-3 proteins are a highly conserved family of proteins whose functions include regulation of protein folding, neuronal architecture, and synaptic function. Additionally, 14-3-3s interact with both Aβ and tau, and reduced levels of 14-3-3s have been shown in the brains of AD patients and in AD mouse models. Here, we examine the neuroprotective potential of the 14-3-3θ isoform in AD models. We demonstrate that 14-3-3θ overexpression is protective and 14-3-3θ inhibition is detrimental against oligomeric Aβ-induced neuronal death in primary cortical cultures. Overexpression of 14-3-3θ using an adeno-associated viral (AAV) vector failed to improve performance on behavioral tests, improve Aβ pathology, or affect synaptic density in the J20 AD mouse model. Similarly, crossing a second AD mouse model, the AppNL-G-F knock-in (APP KI) mouse, with 14-3-3θ transgenic mice failed to rescue behavioral deficits, reduce Aβ pathology, or impact synaptic density in the APP KI mouse model. 14-3-3θ is likely partially insolubilized in the APP models, as demonstrated by proteinase K digestion. These findings do not support increasing 14-3-3θ expression as a therapeutic approach for AD.

Keywords: 14-3-3; Alzheimer’s disease; cortex; hippocampus; mouse model; β-amyloid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • tau Proteins