期刊
CELL
卷 126, 期 4, 页码 775-788出版社
CELL PRESS
DOI: 10.1016/j.cell.2006.06.046
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资金
- NIA NIH HHS [AG008702] Funding Source: Medline
- NINDS NIH HHS [NS015076] Funding Source: Medline
The neuronal ubiquitin/proteasomal pathway has been implicated in the pathogenesis of Alzheimer's disease (AD). We now show that a component of the pathway, ubiquitin C-terminal hydrolase L1 (Uch-L1), is required for normal synaptic and cognitive function. Transduction of Uch-L1 protein fused to the transduction domain of HIV-transactivator protein (TAT) restores normal enzymatic activity and synaptic function both in hippocampal slices treated with oligomeric A beta and in the APP/PS1 mouse model of AD. Moreover, intraperitoneal injections with the fusion protein improve the retention of contextual learning in APP/PS1 mice over time. The beneficial effect of the Uch-L1 fusion protein is associated with restoration of normal levels of the PKA-regulatory subunit II alpha, PKA activity, and CREB phosphorylation.
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