Delta-secretase triggers Alzheimer's disease pathologies in wild-type hAPP/hMAPT double transgenic mice

• Type of Material: Article
• Authors: Zhourui Wu, Emory University; Xia Liu, Emory University; Liming Cheng, Emory University; Keqiang Ye, Emory University
• Language: English
• Date: 2020-12-12
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41419-020-03270-7
• Title of Journal or Parent Work: CELL DEATH & DISEASE
• Volume: 11
• Issue: 12
• Start Page: 1058
• End Page: 1058
• Grant/Funding Information: This study was supported in part by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities (P30NS055077). Further support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. This work was supported by grants from NIH grant (RF1, AG051538) to K.Y., the Funds for International Cooperation and Exchange of the NSFC (81810001048), the National Basic Research Program of China (No. 2016YFA0100800) to L.C., Shanghai Pujiang Program (No. 19PJ1409200) and the National Natural Science Foundation of China (No. 82071370) to Z.W.
• Keywords: TAU; TANGLE; NEURON; Cell Biology; IMMUNOTHERAPY; EXPRESSION; DUPLICATION; Life Sciences & Biomedicine; PHOSPHORYLATION; APP; PHENOTYPE; COGNITIVE DEFICITS; Science & Technology
• Research Categories: Engineering, Biomedical; Biology, Cell

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease with multifactorial pathologies including Aβ containing senile plaques and neurofibrillary tangles (NFT) consisted of aggregated Tau. Most of the AD patients are sporadic and the familial mutation hereditary patients are composed only 1% of all cases. However, the current AD mouse models employ mutated APP, PS1, or even Tau mutant, in order to display a portion of AD pathologies. Delta-secretase (legumain, or asparaginyl endopeptidase, AEP) simultaneously cleaves both APP and Tau and augments Aβ production and Tau hyperphosphorylation and aggregation, contributing to AD pathogenesis. Here we show that δ-secretase is sufficient to promote prominent AD pathologies in wild-type hAPP/hMAPT double transgenic mice. We crossed hAPP l5 mice and hMAPT mice to generate double transgenic mouse model carrying both human wild-type APP and Tau. Compared to the single transgenic parents, these double transgenic mice demonstrated AD-related pathologies in one-year-old hAPP/hMAPT mice. Notably, overexpression of δ-secretase in hAPP/hMAPT double-transgenic mice evidently accelerated enormous senile plaques and NFT, associated with prominent synaptic defects and cognitive deficits. Hence, δ-secretase facilitates AD pathogenesis independent of any patient-derived mutation.