Wednesday, December 31, 2025 12/31/2025

miR-29: A brain homeostasis molecule for Alzheimer’s disease prevention

Award Number: R01AG082140
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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miR-29: A brain homeostasis molecule for Alzheimer’s disease prevention - Project Summary One of the underexplored aspects of neuronal biology is that as postmitotic neurons become mature, they undergo dynamic changes to ensure that the mature nervous system is capable of long-term survival and function. Understanding these mechanisms that are critical for the long-term homeostasis of the adult brain is important as their dysfunction could increase the vulnerability of neurons to age-related neurodegeneration, such as Alzheimer’s disease (AD). We have identified miR-29 as a microRNA that is strikingly induced during brain maturation. In contrast to the high miR-29 levels that are maintained in the normal adult brains, miR-29 levels are reduced in Alzheimer’s Disease patients. miR-29 is recognized to target many of the genes in the AD pathways including BACE1, NAV3, and IFITM3. To evaluate the functional importance of miR-29, we generated mice in which miR-29 can be conditionally deleted. Mice deficient for miR-29 in the brain are born normal but then progressively decline, exhibiting neurological defects and early lethality. These results show that miR-29 is physiologically important for the maintenance of long-term homeostasis in the adult brain. Reduction in miR-29 levels could therefore increase the vulnerability of mature neurons to become dysfunctional in the context of AD. We have recently generated mice in which miR-29 levels can be conditionally reduced in the adult brain. Thus, the overall focus of our proposal is to define the consequences of miR-29 reduction in the adult brain and to evaluate the therapeutic potential of miR-29 for AD. Specifically, in Aim 1, we will conduct single-cell RNA- seq analysis to identify the specific cell types that are most impacted by miR-29 reduction in the adult brain. We will also examine if miR-29 reduction causes changes in dendritic spine morphology and neuronal arborization in the adult brain. Our results have revealed that an essential function of miR-29 is to regulate non-canonical (non-CG), CH methylation in the mature brain via its targeting of the methyltransferase Dnmt3a, where the loss of miR-29 results in CH hypermethylation and reprogramming of gene expression. In Aim 2, we will examine if CH hypermethylation is a common feature of AD in three distinct mouse models of AD and AD patient brain samples. Our hypothesis is that restoring miR-29 levels would have therapeutic benefit for AD. Thus, in Aim 3, we will examine whether AAV-mediated delivery of miR-29 confers benefit in human stem cell and preclinical mouse models of AD. Overall, we are excited to be working on a molecule, miR-29, that has a unique and essential function in the mature brain. Our studies will help define its mechanisms of action as well as evaluate its therapeutic potential in the context of Alzheimer’s Disease.


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: 2026 ( Subtotal = $570,149 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	000	4	12/11/2025	NON-COMPETING CONTINUATION	$570,149
														Subtotal = $570,149

Issue Date FY: 2025 ( Subtotal = $620,826 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	001	3	9/23/2025	NON-COMPETING CONTINUATION	$50,677
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	000	3	12/16/2024	NON-COMPETING CONTINUATION	$570,149
														Subtotal = $620,826

Issue Date FY: 2024 ( Subtotal = $622,753 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	001	2	5/6/2024	NON-COMPETING CONTINUATION	$62,274
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	000	2	12/14/2023	NON-COMPETING CONTINUATION	$560,479
														Subtotal = $622,753

Issue Date FY: 2023 ( Subtotal = $622,753 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Aging Research	000	1	3/30/2023	NEW	$622,753
														Subtotal = $622,753

Grand Total All Awards = $2,436,481

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miR-29: A brain homeostasis molecule for Alzheimer’s disease prevention

Award Number: R01AG082140

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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