Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory

  • Cell. 2006 Aug 25;126(4):775-88. doi: 10.1016/j.cell.2006.06.046.
Bing Gong  1 ,  Zixuan Cao ,  Ping Zheng ,  Ottavio V Vitolo ,  Shumin Liu ,  Agnieszka Staniszewski ,  Donna Moolman ,  Hong Zhang ,  Michael Shelanski ,  Ottavio Arancio
Affiliations
  • 1. Department of Pathology and Taub Institute, Columbia University, New York, NY 10032, USA.
PMID: 16923396 DOI: 10.1016/j.cell.2006.06.046
Abstract

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 Abeta 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 IIalpha, PKA activity, and CREB phosphorylation.

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