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Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory.
- Source :
-
Cell [Cell] 2006 Aug 25; Vol. 126 (4), pp. 775-88. - Publication Year :
- 2006
-
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.
- Subjects :
- Alzheimer Disease enzymology
Amyloid beta-Protein Precursor genetics
Animals
Avoidance Learning
Cyclic AMP Response Element-Binding Protein metabolism
Cyclic AMP-Dependent Protein Kinases metabolism
Disease Models, Animal
Excitatory Postsynaptic Potentials physiology
Fear
Gene Products, tat genetics
Gene Products, tat metabolism
Hippocampus cytology
Hippocampus metabolism
Humans
In Vitro Techniques
Long-Term Potentiation physiology
Membrane Proteins genetics
Membrane Proteins metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Presenilin-1
Recombinant Fusion Proteins genetics
Ubiquitin Thiolesterase genetics
Alzheimer Disease physiopathology
Amyloid beta-Protein Precursor metabolism
Memory physiology
Recombinant Fusion Proteins metabolism
Synaptic Transmission physiology
Ubiquitin Thiolesterase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0092-8674
- Volume :
- 126
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 16923396
- Full Text :
- https://doi.org/10.1016/j.cell.2006.06.046