Role of PDE2A in mitochondrial dysfunction in Alzheimer’s disease

PROJECT SUMMARY/ABSTRACT Compelling evidence suggests that mitochondrial dysfunction is an early feature in susceptible neurons in the brains of patients with Alzheimer’s disease (AD) and plays a critical role in pathogenesis, yet the underlying molecular mechanisms remain incompletely understood. Phosphodiesterases (PDEs) are a superfamily of enzymes responsible for the hydrolysis of cAMP and cGMP, second messengers that regulate important cellular functions. Interestingly, recent studies demonstrated that cAMP/cGMP-PKA/PKG signaling is involved in the regulation of mitochondrial dynamics and expression/assembly of key enzymes in the electron transport chain (ETC) and mitochondrial respiration. Among the many PDEs, PDE2A is the most highly expressed PDE in the hippocampus and frontal/temporal cortex, brain regions vulnerable to AD. Our preliminary studies found increased PDE2A expression in the brains of AD patients and APP/PS1 mice (an AD model), accompanied by decreased cAMP and cGMP in both cytosol and mitochondria matrix, implicating the potential involvement of an aberrant PDE2A-cAMP/cGMP signaling in the pathogenesis of AD. Multiple studies, including ours, demonstrated cognitive enhancing effect of PDE2A inhibitors, although the underlying mechanism remains elusive. In this regard, our preliminary studies revealed that PDE2A overexpression impaired mitochondrial function accompanied by extensive mitochondrial fragmentation. Importantly, Aβ-induced mitochondrial fragmentation and respiratory deficits could be rescued by a PDE2A inhibitor, suggesting mitochondrial dynamics and function could be mechanism of action for PDE2A to influence cognition. Based on these studies, we hypothesized that aberrant PDE2A signaling caused mitochondrial dysfunction which adversely impacted neuronal/synaptic function and caused pathological/cognitive deficits in AD. Novel animal models with PDE2A conditional knockout in the forebrain will be crossed with different AD transgenic mouse models and carefully characterized. The role of PDE2A2, the PDE2A isoform uniquely localized to mitochondria, in brain function and behavior in AD mouse models will also be determined. Finally, based on the literature and our preliminary study, we propose to explore the mechanism underlying the effects of aberrant PDE2A expression on mitochondrial dysfunction with a focus on mitochondrial dynamics and the expression/assembly of mitochondrial ETC complexes. Our proposed studies will provide mechanistic insights into molecular mechanisms underlying mitochondrial dysfunction in AD and deepen our understanding of PDE2A in the regulation of cognition in the brain. The successful completion of this study will likely pave the way for future drug development of PDE2A inhibitors, specifically for the mitochondrial PDE2A2 isoform, as a promising treatment for AD.