TY - JOUR T1 - 14-3-3θ Does Not Protect against Behavioral or Pathological Deficits in Alzheimer’s Disease Mouse Models JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0368-21.2022 VL - 9 IS - 3 SP - ENEURO.0368-21.2022 AU - Mary Gannon AU - Bing Wang AU - Sara Anne Stringfellow AU - Stephan Quintin AU - Itzel Mendoza AU - Thanushri Srikantha AU - A. Claire Roberts AU - Takashi Saito AU - Takaomi C. Saido AU - Erik D. Roberson AU - Talene A. Yacoubian Y1 - 2022/05/01 UR - http://www.eneuro.org/content/9/3/ENEURO.0368-21.2022.abstract N2 - 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. ER -