Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 16, 2018 (received for review September 14, 2018)
Our most recent reports demonstrate that δ-secretase (AEP) cleaves both APP and Tau, promoting Ab and neurofibrillary tangle formation. Depletion of δ-secretase diminishes Alzheimer’s disease (AD) pathologies and restores cognitive functions in AD mouse models. Moreover, we found that C/EBPβ, an inflammatory cytokine or Ab-activated transcription factor, dictates δ-secretase expression during aging. Overexpression of C/EBPβ facilitates AD pathologies via upregulating δ-secretase, whereas depletion of C/EBPβ reduces AD pathologies. In the current study, we examined the pathological roles of the C/EBPβ/δ-secretase axis in different AD mouse models, at different time points, and in different brain regions and found that this pathway plays a critical role in mediating AD pathologies and cognitive function. Hence, C/EBPβ/δ-secretase spatiotemporally mediates AD pathogenesis.
Alzheimer’s disease (AD) neuropathological hallmarks include senile plaques with aggregated amyloid beta as a major component, neurofibrillary tangles (NFT) containing truncated and hyperphosphorylated Tau, extensive neuronal loss, and chronic neuroinflammation. However, the key molecular mechanism that dominates the pathogenesis of AD remains elusive for AD. Here we show that the C/EBPβ/δ-secretase axis is activated in an age-dependent manner in different brain regions of the 3×Tg AD mouse model, elevating δ-secretase–truncated APP and Tau proteolytic truncates and promoting senile plaques and NFT formation in the brain, associated with gradual neuronal loss and chronic neuroinflammation. Depletion of inflammatory cytokine-regulated transcription factor C/EBPβ from 3×Tg mice represses APP, Tau, and δ-secretase expression, which subsequently inhibits APP and Tau cleavage, leading to mitigation of AD pathologies. Knockout of δ-secretase from 3×Tg mice strongly blunts AD pathogenesis. Consequently, inactivation of the C/EBPβ/δ-secretase axis ameliorates cognitive dysfunctions in 3×Tg mice by blocking APP and Tau expression and their pathological fragmentation. Thus, our findings support the notion that C/EBPβ/δ-secretase axis plays a crucial role in AD pathogenesis.
Author contributions: S.C. and K.Y. designed research; H.W. performed research; X.L. contributed new reagents/analytic tools; H.W. analyzed data; and S.C. and K.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1815915115/-/DCSupplemental.
Published under the PNAS license.
