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Decoding the modified small RNAs that drive TLR7/8-mediated neuroinflammation in Alzheimer’s disease

Award Number: K99AG097921
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/11/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Decoding the modified small RNAs that drive TLR7/8-mediated neuroinflammation in Alzheimer’s disease - Project Summary: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by cognitive decline and chronic neuroinflammation, yet the molecular triggers driving this inflammation remain only partially understood. Emerging studies suggest endogenous small RNAs, particularly tRNA-derived (tsRNAs) and rRNA-derived (rsRNAs) small RNAs, can activate innate immune toll-like receptors (TLR7/8), traditionally known as sensors of exogenous viral RNAs. Our preliminary data show that (i) RNA extracted from postmortem human AD brains significantly induces proinflammatory cytokines (e.g., TNF-α, IL-6) in microglia compared to control brain RNA; (2) our pilot PANDORA-seq study on human AD Medial Frontal Gyrus (MFG) revealed significantly dysregulated subsets of tsRNAs/rsRNAs compared to controls; and (3) our prior work showed altered sncRNA modification patterns in AD brains. These convergent findings, alongside similar observations using RNA from aged mouse brains, strongly support our central hypothesis: Specific subsets of tsRNAs/rsRNAs, bearing distinct chemical modifications and altered during aging and AD pathogenesis, act as potent endogenous ligands driving TLR7/8-mediated neuroinflammation in AD. Our overarching goal of this proposal is to define how tsRNA/rsRNA dynamics and their modifications contribute to TLR-triggered inflammation in the context of aging and AD. We will leverage two innovative technologies: PANDORA-seq, which is an advanced method that captures a broader landscape of modified small RNAs, including highly modified tsRNAs and rsRNAs previously undetectable by traditional method; and MLC-seq, a mass spectrometry–based approach that identify precise modification patterns of small RNAs. By integrating these cutting-edge sequencing approaches with functional assays assessing TLR activation in human iPSC- derived microglia and validation in AD mouse models, we will pinpoint specific sncRNA species and modifications critical to the neuroinflammatory process. This research promises to elucidate novel pathogenic drivers of AD-related inflammation and identify potential therapeutic avenues targeting sncRNA-TLR interactions. Under the mentorship of Dr. Qi Chen (tsRNA/rsRNA biology expert) and Dr. Johannes Schlachetzki (microglial function, human brain bank access), supported by a multidisciplinary advisory committee, this project provides an ideal platform to develop the necessary skills and networks for launching an independent research program focused on sncRNA-mediated neuroinflammation in AD. The University of Utah provides an outstanding training environment to facilitate this transition.


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 = $116,764 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Aging Research	000	1	9/11/2026	NEW	$116,764
														Subtotal = $116,764

Grand Total All Awards = $116,764

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Decoding the modified small RNAs that drive TLR7/8-mediated neuroinflammation in Alzheimer’s disease

Award Number: K99AG097921

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/11/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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