Monday, August 18, 2025 8/18/2025

The role of N6-methyladenosine modified RNA in Alzheimer's disease

Award Number: R01AG080810
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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The role of N6-methyladenosine modified RNA in Alzheimer's disease - The accumulation of oligomeric tau (oTau) is known to drive the pathophysiology of Alzheimer’s disease (AD) and related disorders. We recently discovered that oTau functions as part of the translational stress response, forming a complex with methylated RNA (N6-methyl adenosine, m6A) through adapter proteins, such as HNRNPA2B1, which is itself a risk factor for amyotrophic lateral sclerosis. m6A is known to regulate RNA degradation and utilization, and the m6A modification is “read” by adapter proteins. This complex accumulates in stress granules along with other RNA binding proteins (RBPs), many of which are also risk factors for neurodegenerative diseases. We observe a strong increase of m6A in AD which highlights the importance of epi-transcriptomics in AD. The m6A pathway provides a powerful new path to elucidate mechanisms of neurodegeneration. The m6A axis also provides an innovative, putative therapeutic target for AD because our studies using an iPSC-based model of AD show that reducing m6A levels reduces tau pathology and delays disease progression, suggesting returning m6A to basal levels is beneficial. Multiple stresses (e.g., β-amyloid (Aβ) aggregation, AD risk genes, vascular dysfunction, inflammation, and aging) converge to drive the pathophysiology of AD. Analyzing stress responses through the lens of RNA metabolism and the translational stress response provides a vast tool of molecules for elucidating the stress response in AD. Some RBPs, such as TIA1, HRNPA2B1, and tau appear to be required for responses to synaptic stress, while other RBPs, such as FUS, appear to respond mostly to genotoxic damage. Many RBPs exhibit genetic changes that are linked to neurodegenerative diseases, which emphasizes their disease relevance. The m6A tag links RBPs with RNA metabolism. Sequencing m6A labeled transcripts provides an additional powerful approach to identify the particular m6A labeled RNA species that respond to stresses and disease. Transcripts showing particularly large disease-related changes in m6A could provide the basis for new disease biomarkers or represent potential targets for disease-modifying gene therapy. We hypothesize that increases in m6A occur early in the disease course in response to tau pathology, enhance the translational stress response and accelerate neurodegeneration. The studies below will determine which molecular and pathological changes correlate most closely with m6A levels, and which show the most dynamic response to m6A reduction. Aim 1 will determine how the m6A transcriptome over the disease course in mouse models of AD/ADRD, examining both coding and non-coding RNA. Aim 2 will determine how the m6A transcriptome varies by disease severity and type in human pathological cases. Aim 3 will determine how m6A contributes to the pathophysiology of tau and neurodegeneration in 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 = $780,961 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	3	11/22/2024	NON-COMPETING CONTINUATION	$717,209
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	001	3	8/4/2025	NON-COMPETING CONTINUATION	$63,752
														Subtotal = $780,961

Issue Date FY: 2024 ( Subtotal = $783,699 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	001	2	5/1/2024	NON-COMPETING CONTINUATION	$78,370
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	2	12/4/2023	NON-COMPETING CONTINUATION	$705,329
														Subtotal = $783,699

Issue Date FY: 2023 ( Subtotal = $862,531 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	1	12/5/2022	NEW	$806,543
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	001	1	5/8/2023	SUPPLEMENT FOR EXPANSION	$55,988
														Subtotal = $862,531

Grand Total All Awards = $2,427,191

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The role of N6-methyladenosine modified RNA in Alzheimer's disease

Award Number: R01AG080810

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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