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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • 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
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Presenilin-1
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Synaptic Transmission / physiology*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • Cyclic AMP Response Element-Binding Protein
  • Gene Products, tat
  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • Recombinant Fusion Proteins
  • UCHL1 protein, human
  • Cyclic AMP-Dependent Protein Kinases
  • Ubiquitin Thiolesterase
  • Uchl1 protein, mouse