Abstract
Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4, 5 and 9 could alleviate the cytotoxic effects of amyloid beta 1–42 (Aβ1–42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4, 5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the colocalisation between the chaperone and Aβ1–42 to significantly decrease the toxic effect of the peptide. We conclude that inhibition of PDE9 is most effective to combat Aβ1–42 cytotoxicity in our cell model.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in the elderly and numerous studies have shown the amyloid beta (Ab) peptide to be a key toxic component in AD
In the context of AD, increases in Cyclic AMP (cAMP) and cyclic GMP (cGMP) triggered by selective inhibition of PDE4 [19], PDE5 [20] and PDE9 [21] have been responsible for improved synaptic function and memory in AD rodent models
Another protein that can be phosphorylated by protein kinase A (PKA)/protein kinase G (PKG) and confers protection in AD is the small heatshock protein heatshock protein 20 (HSP20)
Summary
Alzheimer’s disease (AD) is the most common form of dementia in the elderly and numerous studies have shown the amyloid beta (Ab) peptide to be a key toxic component in AD. The superfamily of phosphodiesterases (PDEs) is an attractive target for modulating synaptic plasticity via second messenger signalling as these enzymes provide the sole means of cyclic nucleotide degradation. A number of PDEs have been associated with signalling pathways involved in Abbreviations AD, Alzheimer’s disease; Ab, amyloid beta; DMEM, Dulbecco’s Modified Eagle’s Medium; HSP20, heatshock protein 20; PDE, phosphodiesterase; PKA, protein kinase A; PKG, protein kinase G. HSP20 attenuates amyloid beta 1–42-mediated cytotoxicity neuropsychiatric disorders, PDE4, PDE5 and PDE9, with the latter two more recently emerging as novel therapeutic targets for AD [7]
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