Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory.
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.
Gong
Bing
B
Department of Pathology and Taub Institute, Columbia University, New York, NY 10032, USA.
Cao
Zixuan
Z
Zheng
Ping
P
Vitolo
Ottavio V
OV
Liu
Shumin
S
Staniszewski
Agnieszka
A
Moolman
Donna
D
Zhang
Hong
H
Shelanski
Michael
M
Arancio
Ottavio
O
D000544:Alzheimer Disease / Q000201:enzymology / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001362:Avoidance Learning; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005239:Fear; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D017362:Cyclic AMP Response Element-Binding Protein; D015696:Gene Products, tat; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011993:Recombinant Fusion Proteins; C482860:UCHL1 protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse