Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment
Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O.
The Center for Dementia Research,
Nathan Kline Institute for Psychiatric Research,
Orangeburg, New York, USA.
Department of Pathology and the Taub Institute for Research
on Alzheimer's Disease and the Aging Brain,
Columbia University, New York, New York, USA.
J Clin Invest. 2004 Dec 1;114(11):1624-1634
ABSTRACTEvidence 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.Rolipram
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