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- W3022271444 abstract "Overproduction and diminished removal of amyloid beta–protein (Aβ) in the brain play a key role in Alzheimer's Disease (AD)–like pathology. Analysis of proteasome function in post–mortem human AD brains has shown a strong inhibition of activity in the proteasome and lower protein levels for the Ubiquitin–C–terminal hydrolaseL1 (Uch–L1), a neuron specific enzyme, suggesting neuronal ubiquitin–proteasomal system is linked to the pathogenesis of AD. However, the role of Uch–L1 in the AD development is not known. To investigate effects of the Uch–L1 on synaptic and cognitive deficits in an animal model of AD, the APP(K670N : M671L)/ PS1(M146L) mouse. Ubiquitin hydrolase (Uch) activity and Uch–L1 protein levels in hippocampus mice were analyzed. Basal synaptic transmission (BST) and long–term potentiation (LTP) were recorded. Contexul fear–conditioning was performed in APP/PS1 mice and WT littermates. Inhibition of Uch–L1 activity through the specific inhibitor LDN–57444 mimics the effect of high levels of amyloid–β both on synaptic function (BST and LTP: 39% and 73% of control vehicle–treated slices, respectively) and contextual learning (freezing time ∼70% of control–vehicle injected mice at 1 and 21 days after the electric shock). Uch activity and Uch–L1 protein level are reduced in the APP/PS1 mice (∼65% of WT littermates). Transduction of Uch–L1 protein, which was fused with the transduction domain of HIV–transactivator protein (TAT), re–establishes both normal synaptic function (BST and LTP: ∼95% and ∼93% of vehicle–treated WT slices, respectively) and decay of contextual learning (∼86% of vehicle–treated WT littermates at 21 days after the electric shock) in APP/PS1 mice. Finally, the beneficial effect of the Uch–L1 fusion protein is linked to restoration of normal levels of PKA regulatory subunit IIα leading to normal kinase activity and CREB phosphorylation. Uch–L1 is essential for normal synaptic and cognitive function. Down–regulation of Uch–L1 function contributes to the deficits of synaptic plasticity and associative learning in the APP/PS1 mouse model of AD." @default.
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- W3022271444 date "2006-07-01" @default.
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- W3022271444 title "P1-043: UCH-L1 is a critical regulator of synaptic and memory functions following amyloid elevation" @default.
- W3022271444 doi "https://doi.org/10.1016/j.jalz.2006.05.418" @default.
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