Cyclic AMP enhancers and Abeta oligomerization blockers as potential therapeutic agents in Alzheimer's disease.
One of the earliest manifestations of Alzheimer's disease (AD) is the characteristic inability of affected individuals to form new memories. Memory impairment appears to significantly predate the death of nerve cells, implying that neuronal dysfunction is responsible for the pathophysiology of early stage AD. Mounting evidence now indicates that soluble oligomers of the amyloid-beta peptide (Abeta) are the main neurotoxins that lead to early neuronal dysfunction and memory deficits in AD. Cyclic AMP (cAMP) is a central component of intracellular signaling pathways that regulate a wide range of biological functions, including memory. Among other actions, cAMP triggers the phosphorylation and activation of the cAMP responsive element binding protein (CREB), a transcription factor that regulates the expression of genes that are important for long-term memory. Here, we discuss recent evidence suggesting that cAMP enhancing compounds may find applications as neurocognitive enhancers in AD and in other neurological disorders, as well as possible roles of cAMP in the regulation of neuronal regeneration. In particular, we review recent results showing that low concentrations of 2,4-dinitrophenol (DNP) upregulate neuronal cAMP and tau levels, promote neurite outgrowth and neuronal differentiation and block the oligomerization and neurotoxicity of Abeta. Possible implications of these findings in the development of novel therapeutic approaches in AD are discussed.
De Felice
Fernanda G
FG
Instituto de Bioquímica Médica, Programa de Bioquímica e Biofísica Celular, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil. felice@bioqmed.ufrj.br
Wasilewska-Sampaio
Ana Paula
AP
Barbosa
Anna Carolina A P
AC
Gomes
Flavia C A
FC
Klein
William L
WL
Ferreira
Sérgio T
ST
D019297:2,4-Dinitrophenol / Q000494:pharmacology / Q000627:therapeutic use*; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D016875:tau Proteins; D000242:Cyclic AMP; D053829:Amyloid Precursor Protein Secretases; D019297:2,4-Dinitrophenol