PT  - JOURNAL ARTICLE
AU  - Gannon, Mary
AU  - Wang, Bing
AU  - Stringfellow, Sara Anne
AU  - Quintin, Stephan
AU  - Mendoza, Itzel
AU  - Srikantha, Thanushri
AU  - Roberts, A. Claire
AU  - Saito, Takashi
AU  - Saido, Takaomi C.
AU  - Roberson, Erik
AU  - Yacoubian, Talene A.
TI  - 14-3-3θ does not protect against behavioral or pathological deficits in Alzheimer’s disease mouse models
AID  - 10.1523/ENEURO.0368-21.2022
DP  - 2022 Jun 10
TA  - eneuro
PG  - ENEURO.0368-21.2022
4099  - http://www.eneuro.org/content/early/2022/06/10/ENEURO.0368-21.2022.short
4100  - http://www.eneuro.org/content/early/2022/06/10/ENEURO.0368-21.2022.full
AB  - 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.