# NIH grant: Diversity of Phosphodiesterase 2A Signaling in Traumatic Brain Injury and Alzheimer’s Disease. (1RF1NS145336-01) — retained record

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NIH grant 1RF1NS145336-01: Diversity of Phosphodiesterase 2A Signaling in Traumatic Brain Injury and Alzheimer’s Disease.
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: COLEEN M. ATKINS. Award: $1840615.
Start: 2026-09-05T00:00:00.
PROJECT SUMMARY/ABSTRACT
Mitochondrial dysfunction is an early feature in susceptible neurons of patients with traumatic brain injury (TBI)
and its progression to Alzheimer’s disease (AD) and related dementia (ADRD), while the underlying
mechanisms remain elusive. The goal of this project is to determine the role of phosphodiesterase 2A
(PDE2A) in mitochondrial bioenergetic failure by modulating voltage dependent anion channel 1 (VDAC1)
phosphorylation, gating behavior, and mitochondrial DNA (mtDNA) leakage. Moreover, the project aims to
elucidate how VDAC1 phosphorylation and oligomerization contribute to neuroinflammation and
neurodegeneration following traumatic brain injury (TBI) and its progression to Alzheimer's disease (AD).
cAMP and/or cGMP signaling plays a crucial role in regulating the expression of key enzymes in the electron
transport chain (ETC), thereby affecting respiratory chain function. As a major hydrolase of cAMP and cGMP,
PDE2A expression is found to be increased in the brains of AD patients and mice subjected to TBI, prior to the
onset of AD-associated cognitive deficits. This increase in PDE2A is concomitant with decreased cAMP and
cGMP in both the cytosol and mitochondria. Further study has shown that TBI-induced mitochondrial nucleoid
DNA (mtDNA) leakage and respiratory deficits could be rescued by a PDE2A inhibitor, suggesting a novel role
of PDE2A in homeostasis imbalance in the cognitive processing. PDE2A deficiency promotes protein kinase A
(PKA)-mediated VDAC1 phosphorylation, which may reduce VDAC1 oligomerization and improve
mitochondrial metabolite transport. Among the three PDE2A isoforms, PDE2A2 contains a unique N-terminal
17-amino-acid sequence that specifically targets it to mitochondria. This localization makes PDE2A2 the
unique isoform involved in regulating local cyclic nucleotide signaling. By hydrolyzing cAMP and/or cGMP,
PDE2A2 impacts mitochondrial functional integrity by negatively regulating VDAC1 phosphorylation,
modulating its gating behavior, and ultimately controlling cell fate. Thus, we hypothesize that TBI-activated
PDE2A (PDE2A2)-VDAC1 axis contributes to mitochondrial dysfunction by altering VDAC1 phosphorylation,
oligomerization, and gating behavior, as well as inducing mtDNA leakage. These changes, in turn, trigger
neuroinflammation and exacerbate pathological and cognitive deficits associated with AD and dementia. Our
group has established novel animal models, i.e. forebrain specific PDE2A knockout and functional PDE2A2
knockout mice crossed to AD mice. Using these mouse models, we will investigate the mechanism underlying
the effects of aberrant PDE2A, particularly PDE2A2, on neuroinflammation and neurodegeneration with a
focus on VDAC1 phosphorylation, oligomerization, gating behavior, and mitochondrial homeostasis. This
project will provide mechanistic insights into PDE2A-VDAC1 axis underlying mitochondrial dysfunction in TBI
associated with AD/ADRD and enhance our understanding of PDE2A’s role in regulating cognition in the brain.
```



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