期刊
CELL DEATH & DISEASE
卷 11, 期 12, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-020-03270-7
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资金
- Rodent Behavioral Core (RBC) - Emory University School of Medicine
- Viral Vector Core of the Emory Neuroscience NINDS Core Facilities [P30NS055077]
- Georgia Clinical & Translational Science Alliance of the National Institutes of Health [UL1TR002378]
- NIH grant (RF1) [AG051538]
- Funds for International Cooperation and Exchange of the NSFC [81810001048]
- National Basic Research Program of China [2016YFA0100800]
- Shanghai Pujiang Program [19PJ1409200]
- National Natural Science Foundation of China [82071370]
Alzheimer's disease (AD) is the most common neurodegenerative disease with multifactorial pathologies including A beta 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 A beta production and Tau hyperphosphorylation and aggregation, contributing to AD pathogenesis. Here we show that delta -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 delta -secretase in hAPP/hMAPT double-transgenic mice evidently accelerated enormous senile plaques and NFT, associated with prominent synaptic defects and cognitive deficits. Hence, delta -secretase facilitates AD pathogenesis independent of any patient-derived mutation.
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