RRC ID 71758
Author Gannon M, Wang B, Stringfellow SA, Quintin S, Mendoza I, Srikantha T, Roberts AC, Saito T, Saido TC, Roberson ED, Yacoubian TA.
Title 14-3-3θ Does Not Protect against Behavioral or Pathological Deficits in Alzheimer's Disease Mouse Models.
Journal eNeuro
Abstract Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with synaptic dysfunction and dendritic spine loss and the pathological hallmarks of amyloid beta (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 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.Significance StatementDespite being the most common form of neurodegeneration, effective treatments for Alzheimer's disease (AD) remain elusive and therefore novel therapeutic targets are needed. 14-3-3 proteins, a highly conserved family of chaperone proteins involved in regulating synaptic function and neuronal architecture, are reduced in human AD patients, making them a promising novel target. In this study, we examined the effects of increasing the 14-3-3θ isoform in AD models. We observed that 14-3-3θ overexpression reduces oligomeric Aβ toxicity in cortical cultures. However, increasing the 14-3-3θ expression in two different AD mouse models failed to rescue behavioral or pathological phenotypes, indicating a more complicated relationship between 14-3-3s and AD.
Volume 9(3)
Published 2022-1-1
DOI 10.1523/ENEURO.0368-21.2022
PII ENEURO.0368-21.2022
PMID 35697511
PMC PMC9233504
MeSH 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
IF 3.544
Mice RBRC06344