14-3-3ζ Captures SET in the Cytoplasm, Mediating Tau Pathology and Cognitive Impairments

Abstract Background: 14-3-3ζ is overexpressed in brain regions affected by tau pathology in Alzheimer’s disease (AD), and its expression correlates with disease progression. The nuclear protein SET is a specific and efficient endogenous inhibitor of PP2A, which acts as a major protein phosphatase regulating tau phosphorylation and is compromised in AD. However, whether 14-3-3ζ mediates the cytoplasmic retention of SET and its related downstream events in AD remains elusive. Methods: We performed Spearman correlation analysis between 14-3-3 and SET in normal control brains and AD brains in a large-scale proteomic study of AD, and observed the distribution of SET and 14-3-3 in AD brain neurons, thus finding the cytoplasmic retention event of SET. We synthesized the peptides that prevented SET from binding to 14-3-3, and evaluated the effects of these peptides in blocking tau pathology. Results: Here, we reported that there is a significant increase in 14-3-3ζ interaction with SET during aging in 3´Tg AD mice and the human AD brain. 14-3-3ζ captures and sequesters SET in the cytoplasm and subsequently inhibits PP2A activity, induces tau hyperphosphorylation and triggers neurodegeneration, leading to behavioral impairments in mice infected with adeno-associated virus encoding 14-3-3ζ. Interestingly, as a dimer and scaffold protein, 14-3-3ζ was found to bind to SET while simultaneously recruiting CKII, which induced SET phosphorylation and cytoplasmic retention. Conversely, silencing 14-3-3ζ impeded CKII phosphorylation of SET. Moreover, blocking the 14-3-3ζ interaction with SET with the peptide NESGDPSSKST substantially induced SET translocation back to the nucleus, augmented PP2A activity and subsequently led to reduced tau hyperphosphorylation, decreased synapse loss and rescue of cognitive deficits in 14-3-3ζ mice. Furthermore, the peptide NESGDPSSKST but not the scramble peptide attenuated tau pathology and cognitive deficits in a 3´Tg AD mouse model. Conclusions: Our data strongly indicate that 14-3-3ζ captures SET in the cytoplasm and simultaneously recruits CKII, and this interaction plays a critical role in mediating tau-related clinical and neuropathological alterations. Inhibition of the 14-3-3ζ interaction with SET may be therapeutically useful for treating AD.