Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment.
J Clin Invest
; 114(11): 1624-34, 2004 Dec.
Article
em En
| MEDLINE
| ID: mdl-15578094
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores de Fosfodiesterase
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Cognição
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Transmissão Sináptica
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Rolipram
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Doença de Alzheimer
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article