Tuesday, November 4, 2025 11/4/2025

Role of PDE2A in mitochondrial dysfunction in Alzheimer’s disease

Award Number: R01AG070873
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $721,300 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	5	6/13/2025	NON-COMPETING CONTINUATION	$58,882
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	000	5	4/2/2025	NON-COMPETING CONTINUATION	$662,418
														Subtotal = $721,300

Issue Date FY: 2024 ( Subtotal = $752,468 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	002	4	4/29/2024	NON-COMPETING CONTINUATION	$752,468
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	3	12/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$816,754
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	2	12/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$816,754
														Subtotal = $752,468

Issue Date FY: 2023 ( Subtotal = $764,388 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	003	3	4/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$764,388
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	002	2	4/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	001	2	1/13/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$599,263
2023	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Aging Research	000	1	1/13/2023	NEW	-$599,263
														Subtotal = $764,388

Issue Date FY: 2022 ( Subtotal = $789,176 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	001	2	5/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$784,331
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	002	2	6/7/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$4,845
2022	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Aging Research	000	1	5/13/2022	NEW	$0
														Subtotal = $789,176

Issue Date FY: 2021 ( Subtotal = $799,872 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Aging Research	000	1	8/9/2021	NEW	$799,872
														Subtotal = $799,872

Grand Total All Awards = $3,827,204

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Role of PDE2A in mitochondrial dysfunction in Alzheimer’s disease

Award Number: R01AG070873

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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