Abstract
BACKGROUND: The failure to find effective therapies in the past two decades underscores the challenge and the urgent need for identifying novel targets against Alzheimer's disease (AD). Cyclic nucleotide phosphodiesterase 2 (PDE2) is a "druggable target" which has more advantage than currently developed PDE4 and PDE5 inhibitors due to fewer side effects. AIMS & OBJECTIVES: The overall objective of this proposal is to investigate the role of PDE2 in mediating mitochondrial dysfunction and neurodegeneration, which should provide the rationale for future research toward developing potential PDE2 inhibitor, particularly mitochondrial PDE2 inhibitor, for the treatment of AD/ADRD. METHODS: The forebrain PDE2 conditional knockout (PDE2 cKO) mice were crossed with APP/PS1 mice which were routinely generated in our laboratory to investigate the role of PDE2 in mediating mitochondrial dysfunction and neurodegeneration. A functional PDE2A2 conditional knockout mouse model was also used where all PDE2A isoforms were knockout but re-expressed full length PDE2A2 (f2A2). They were crossed with AD mouse models to determine whether mitochondrial defects and AD- related deficits were alleviated. In addition, hippocampal neuronal cells were cultured to explore how aberrant PDE2A signaling mediated Aβ-induced mitochondrial deficits in vitro. RESULTS: Immunoblot analysis showed that decreased PDE2 expression in the hippocampus of APP/PS1 mice (APS) crossed with PDE2 cKO mice (APS/2KO) along with increased cAMP/cGMP and pDLP1 levels. While amyloid plaque loads as detected by thioflavin-S staining were significantly reduced in both the hippocampus and cortex of the APS/2KO vs. APS mice. Importantly, APS/2KO mice demonstrated improved cognitive function in both male and female mice as measured by the novel object recognition (NOR) test. Further study showed that the increased dendritic lengths and spine density in the APS/2KO mice were reversed by functional PDE2A2 knockin in the forebrain. These results were consistent with the in vitro findings that suggested that PDE2A2 is sufficient to be responsible for mitochondrial cAMP/cGMP signaling in the hippocampal neuronal cells. The in vitro study showed that aberrant PDE2A2 signaling is responsible for regulation of/cGMP mediated Abeta 42-induced mitochondrial deficits. DISCUSSION &CONCLUSION: The in vivo studies were consistent with the in vitro findings that suggested that aberrant PDE2A2 mediated Abeta 42-induced mitochondrial dysfunction and neuronal deficits. This provides a means to causally link target engagement of PDE2A2 in mitochondria to its effects on brain function and behavior in AD mouse models. This study likely paves the way for future drug development of PDE2 inhibitors, particularly for the mitochondrial PDE2A2 isoform, as novel therapeutics for AD/ADRD.