期刊
BIOFACTORS
卷 48, 期 5, 页码 1111-1117出版社
WILEY
DOI: 10.1002/biof.1847
关键词
cyclic adenosine monophosphate; GEBR-7b; phosphodiesterase inhibitors; tau protein
资金
- Universita degli Studi di Genova
Tau protein can form hyperphosphorylated aggregates in neurodegenerative diseases like Alzheimer's, and phosphorylation of tau by cAMP-dependent protein kinase A (PKA) at Ser214 reduces its pathological assembly. The activation of adenylyl cyclase increases pTAU-S214 levels in N2a cells and rat hippocampal slices, and this effect is mimicked by GEBR-7b, a phosphodiesterase 4D inhibitor.
Tau is a protein that normally participates in the assembly and stability of microtubules. However, it can form intraneuronal hyperphosphorylated aggregates that are hallmarks of Alzheimer's disease and other neurodegenerative disorders known as tauopathies. Tau can be phosphorylated by multiple kinases at several sites. Among such kinases, the cAMP-dependent protein kinase A (PKA) phosphorylates tau at Ser214 (pTAU-S214), an event that was shown to reduce the pathological assembly of the protein. Given that the neuronal cAMP/PKA-activated cascade is involved in synaptic plasticity and memory, and that cAMP-enhancing strategies demonstrated promising therapeutic potential for the treatment of cognitive deficits, we investigated the impact of cAMP on pTAU-S214 in N2a cells and rat hippocampal slices. Our results confirm that the activation of adenylyl cyclase increases pTAU-S214 in both model systems and, more interestingly, this effect is mimicked by GEBR-7b, a phosphodiesterase 4D inhibitor with proven pro-cognitive efficacy in rodents.
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