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Double-stranded RNA in neuronal cell death in Alzheimer's and related neurodegenerative diseases

Award Number: R01AG085307
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Double-stranded RNA in neuronal cell death in Alzheimer's and related neurodegenerative diseases - Project Summary Alzheimer's disease (AD) and related neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are characterized by neuroinflammation and neuronal cell death. Also associated with these diseases is an abnormal deposition of the TDP-43 protein. This protein has multiple roles in RNA metabolism, and we have previously demonstrated that one of its functions is to limit the accumulation of double-stranded RNA (dsRNA). dsRNA rarely accumulates in normal cells (particularly in the cytoplasm), but commonly occurs during viral infection. Thus, abnormal dsRNA is recognized by cells as a sign of infection, leading to the induction of an antiviral innate immune response and the induction of cell death pathways. The central hypothesis we will test in this proposal is that in AD and ALS/FTD the accumulation of dsRNA induces inappropriate activation of antiviral responses that contribute to the observed neuropathology. Our goals are to determine: 1) the underlying molecular mechanisms that lead to dsRNA accumulation, and 2) how dsRNA accumulation leads to glial and neuronal dysfunction. Characterization of pathways that lie both upstream and downstream of dsRNA accumulation in the context of AD, ALS/FTD, and other neurodegenerative diseases has the potential to generate novel therapeutic targets for these currently untreatable pathologies. Our preliminary studies demonstrate that dsRNA accumulates in the hippocampus of Alzheimer's patients and the motor cortex of ALS patients. We will immunopurify and sequence this dsRNA from human brain to determine its origins. Transgenic mouse models with conditional depletion of TDP-43 will be characterized to define the temporal relationships between TDP-43 loss, dsRNA accumulation, gliosis, and neuronal cell death. Infection of human iPSC-derived neural cultures with engineered lentivirus and infection of mouse models with engineered adenovirus will be used to artificially generate dsRNA to investigate the pathways by which dsRNA leads to disease-relevant neuropathology.


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 = $760,995 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	000	2	3/28/2025	NON-COMPETING CONTINUATION	$698,874
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	001	2	6/13/2025	NON-COMPETING CONTINUATION	$62,121
														Subtotal = $760,995

Issue Date FY: 2024 ( Subtotal = $768,931 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	001	1	9/3/2024	NEW	$53,978
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	000	1	6/20/2024	NEW	$714,953
														Subtotal = $768,931

Grand Total All Awards = $1,529,926

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Double-stranded RNA in neuronal cell death in Alzheimer's and related neurodegenerative diseases

Award Number: R01AG085307

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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