14-3-3θ does not protect against behavioral or pathological deficits in Alzheimer’s disease mouse models

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 App^NL-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 Statement

Despite 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.