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Ubiquitin Hydrolase Uch-L1 Rescues β-Amyloid-Induced Decreases in Synaptic Function and Contextual Memory

2006; Cell Press; Volume: 126; Issue: 4 Linguagem: Inglês

10.1016/j.cell.2006.06.046

1097-4172

Bing Gong, Zixuan Cao, Ping Zheng, Ottavio V. Vitolo, Shumin Liu, Agnieszka Staniszewski, Donna Moolman, Hong Zhang, Michael L. Shelanski, Ottavio Arancio,

Ubiquitin and proteasome pathways

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 Aβ 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 IIα, PKA activity, and CREB phosphorylation.