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Transcriptomic Dynamics Associated with TDP-43 Propagation in limbic-predominant age-related TDP-43 encephalopathy neuropathological change

Award Number: R56AG098599
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Transcriptomic Dynamics Associated with TDP-43 Propagation in limbic-predominant age-related TDP-43 encephalopathy neuropathological change - Project Summary: TAR DNA-binding protein 43 (TDP-43) is an essential RNA/DNA-binding protein that regulates RNA processing, alternative splicing, and gene expression. In aging and neurodegenerative disorders, TDP-43 undergoes pathological phosphorylation, ubiquitination, and cytoplasmic aggregation, resulting in neuronal dysfunction and degeneration. In Limbic-predominant Age-related TDP-43 Encephalopathy Neuropathologic Change (LATE-NC), TDP-43 pathology is thought to originate in the amygdala and subsequently involve the hippocampus and other limbic regions. However, the spatial molecular changes associated with early LATE-NC progression remain poorly understood. We hypothesize that stage-dependent TDP-43 pathology is associated with distinct spatial transcriptomic alterations and changes in the local cellular microenvironment during early LATE-NC progression. To test this hypothesis, we will leverage quantitative neuropathology and high-resolution spatial transcriptomics to define molecular changes associated with regional TDP-43 pathology in high Alzheimer's disease neuropathologic change (ADNC) brains with LATE-NC. Our first objective is to map the distribution of pathology (TDP-43, tau, and amyloid-beta) and neuronal loss in AD brains. In Aim 2, we will use spatial sequencing methods to analyze gene expression profiles in brain regions associated with the appearance of TDP-43 proteinopathy. This R56 project will provide new insights into the cellular and molecular mechanisms of LATE 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 = $762,861 )
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Aging Research	000	1	8/21/2026	NEW	$762,861
														Subtotal = $762,861

Grand Total All Awards = $762,861

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Transcriptomic Dynamics Associated with TDP-43 Propagation in limbic-predominant age-related TDP-43 encephalopathy neuropathological change

Award Number: R56AG098599

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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