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, Aß-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.