Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment.
Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels.
Gong
Bing
B
The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.
Vitolo
Ottavio V
OV
Trinchese
Fabrizio
F
Liu
Shumin
S
Shelanski
Michael
M
Arancio
Ottavio
O
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007858:Learning / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D053764:Presenilin-1; D020889:Rolipram / Q000494:pharmacology / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D017362:Cyclic AMP Response Element-Binding Protein; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010726:Phosphodiesterase Inhibitors; D053764:Presenilin-1; D020889:Rolipram