RT Journal Article
SR Electronic
T1 14-3-3θ Does Not Protect against Behavioral or Pathological Deficits in Alzheimer’s Disease Mouse Models
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0368-21.2022
DO 10.1523/ENEURO.0368-21.2022
VO 9
IS 3
A1 Gannon, Mary
A1 Wang, Bing
A1 Stringfellow, Sara Anne
A1 Quintin, Stephan
A1 Mendoza, Itzel
A1 Srikantha, Thanushri
A1 Roberts, A. Claire
A1 Saito, Takashi
A1 Saido, Takaomi C.
A1 Roberson, Erik D.
A1 Yacoubian, Talene A.
YR 2022
UL http://www.eneuro.org/content/9/3/ENEURO.0368-21.2022.abstract
AB 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.