PDE4D inhibitor: a novel weapon against mild cognitive impairment and Alzheimer’s disease?

A classical hallmark of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ), which correlates significantly with progressive cognitive and learning and memory impairment. BPN14770, an allosteric inhibitor of PDE4D, has been proposed to improve memory deficits induced by Aβ oligomers (AβOs) and provide overall AD pathology improvement. However, the causal relationship between PDE4D-related cAMP signaling and the prevalence of AβOs-induced cognitive deficits has not been investigated. The present study examined whether the memory and cognitive enhancing effects of BPN14770 in humanized PDE4D-APP/PS1 (hPDE4D/Tg-AD) mice, which are engineered to express a primate-specific N-terminal region of PDE4D and crossed with transgenic APP/PS1 mice, were directly involved in reduced cAMP signaling dependent amyloid pathway. The results suggested that the PDE4D inhibitor BPN14770 significantly improved cognitive index in novel object recognition task, and memory acquisition and retrieval in Morris water maze test in h hPDE4D/Tg-AD mice. Pretreatment with protein kinase A (PKA) inhibitor H89 completely blocked this BPN14770-induced memory and cognitive enhancement, suggesting the key role of PDE4D dependent cAMP signaling in cognitive processes. Furthermore, the hPDE4D/Tg-AD mice showed increases in Aβ plaque and soluble/insoluble Aβ concentration both in the cortex and hippocampus. While treatment of BPN14770 for two weeks (via gavage) prevented these pathological changes, which can be blocked by H89. The subsequent studies suggested that BPN14770 affected the synthesis and degradation of Aβ as evidenced by decreases in amyloidgenic and non-amyloidgenic pathways such as BACE-1, sAPPβ, ADAM10 and sAPPα protein expression, and increases in Aβ degrading enzymes including IDE and NEP levels, and downstream neuroprotective proteins such as pCREB/CREB and BDNF expression in hAPP/PS1-PDE4D mice. Further chromatin co-immunoprecipitation assays showed cAMP-dependent CREB directly increased ADAM10 and IDE expression, and inhibited BACE-1 expression through NF-κB, resulting in reduction of Aβ production and increase in Aβ degradation. These findings reveal a causal relationship between PDE4D signaling and the progress of AD and demonstrate the clinical potential of BPN14770 in the treatment of AD.