Determining phosphodiesterase 4 isoforms associated with Mild Cognitive Impairment and Alzheimer's disease (R-13225)

The second messenger cyclic adenosine monophosphate (cAMP) is critical in memory consolidation. Targeting cAMP-degrading phosphodiesterase 4 enzymes (PDE4) with an inhibitor is a promising approach for memory enhancement in Alzheimer's disease (AD). However, non-selective PDE4 inhibitors cause side effects such as nausea and vomiting. Preliminary findings show that expression of certain PDE4 isoforms is increased in AD. Therefore, it is hypothesized that a more selective and more timely targeting of PDE4 at the isoform level could improve treatment efficacy and reduce side effects. The goal of this project is to determine which PDE4 isoforms are upregulated via epigenetic changes in patients with AD or its prodromal stage mild cognitive impairment (MCI), and are associated with cognitive decline and pathology. Our findings will be validated using CRISPR/Cas9 methodology in human iPSC-derived neurons (in vitro) and in an AD mouse model (in vivo) for their protective mechanism. Hence, this project will advance the understanding of the cellular and temporal upregulation of PDE4 isoforms in MCI and AD. The obtained knowledge will determine which PDE4 isoform should be inhibited and the exact optimal timing of inhibition.

Keywords:Alzheimer, mild cognitive impairment, phosphodiesterase 4 isoforms

Disciplines:Epigenetics, Cognitive neuroscience, Neurological and neuromuscular diseases, Neurosciences not elsewhere classified