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Defining the pathogenic relationship of TDP-43 inclusions and cytoplasmic double stranded RNA in AD and FTD

Award Number: R01AG078377
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/02/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Defining the pathogenic relationship of TDP-43 inclusions and cytoplasmic double stranded RNA in AD and FTD - Abstract Cytoplasmic inclusions of TDP-43 (TAR DNA-binding protein 43) are found in many patients with Alzheimer's disease (AD). The presence of TDP-43 inclusions predicts a steeper cognitive decline after controlling for other pathologies. TDP-43 cytoplasmic inclusions are also present in > 45% of cases of frontotemporal dementia (FTD), including all cases associated with C9ORF72 repeat expansion, which is the most common genetic mutation causing of FTD. Cytoplasmic aggregates of TDP-43 are hypothesized to sequester the protein from physiological targets, thereby mimicking loss of function mutations in TARDBP that also lead to FTD. Loss of function perturbations of TDP-43 in human cells, mice, Drosophila and C. elegans lead to derepression of endogenous inverted repeat sequences capable of forming double stranded RNA (dsRNA). In preliminary studies, we have found that both AD and FTD human brains with TDP-43 cytoplasmic inclusions have more cytoplasmic dsRNA (cdsRNA), a known activator of type I interferon (IFN-I) signaling. We now propose to investigate the relationship between TDP-43 cytoplasmic inclusions and cdsRNA by extending our analysis to additional AD and FTD brains. We will accomplish this using a method for highly multiplexed microscopy (tissue-based cyclic immunofluorescence; t-CyCIF) developed by our team and recently extended to the analysis of autopsied brains. In Aim 1 we will use t-CyCIF to determine whether TDP-43 inclusions and cdsRNA are coincident in the same cells, and whether they associated with other disease features. We will characterize the inflammatory signatures of astrocytes, microglia, and neurons in the vicinity of cells with TDP-43 inclusions and cdsRNAs. In Aim 2 cdsRNA will be isolated from human AD and FTD brain regions for unbiased next generation sequencing to define each region's dsRNAome. dsRNA sequences will be mapped to the genome using novel methods to determine which dsRNAs arise from endogenous repeat sequences, genomic lesions, and / or viral sequences, particularly members of the Herpes family. In Aim 3 we will study the pathway linking TDP-43 cytoplasmic inclusions to cdsRNA using cultured human iPS- derived neurons from patients with pathogenic TDP-43 mutations and from AD and FTD patients analyzed in Aim 1. We will also elucidate mechanisms of TDP-43 / cdsRNA- mediated neurodegeneration in two mouse models that express TDP-43 mutations and genomically-encoded cdsRNA, and probe the role of IFN-I activation in neuronal death using an FDA-approved JAK inhibitor. By defining the relationship between cytoplasmic TDP-43, dsRNA inclusions, associated inflammatory phenotypes, and neuronal death, our studies will provide new insight into triggers of neuroinflammation of TDP-43 inclusions in AD and FTD. We also aim to nominate inflammatory signatures to identify living patients with cdsRNA- associated AD and FTD pathology who might benefit from a JAK inhibitor in a drug repurposing clinical trial.


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 = $821,162 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	3	7/15/2026	NON-COMPETING CONTINUATION	$821,162
														Subtotal = $821,162

Issue Date FY: 2025 ( Subtotal = $804,740 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	2	8/8/2025	EXTENSION WITH OR WITHOUT FUNDS	$804,740
														Subtotal = $804,740

Grand Total All Awards = $1,625,902

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Defining the pathogenic relationship of TDP-43 inclusions and cytoplasmic double stranded RNA in AD and FTD

Award Number: R01AG078377

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/02/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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