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Epigenetic modulations by sleep to mitigate neurodegeneration

Award Number: K99AG090693
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/15/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Epigenetic modulations by sleep to mitigate neurodegeneration - Project Summary/Abstract Sleep loss is frequently reported early in tauopathies, which are neurodegenerative diseases such as Alzheimer's disease (AD), where abnormally hyperphosphorylated tau protein accumulates in the brain. Extensive evidence suggests a reciprocal relationship between sleep-wake disruption and enhanced tau aggregation, with the accumulation of tau aggregates further disrupting the sleep-wake cycle in both animal models and humans. How sleep loss mechanistically contributes to neurodegeneration remains unknown, which is important as targeting early sleep dysfunction could be the key to combating neurodegenerative diseases. My recent publication demonstrated that subjecting healthy mice to sleep deprivation (SD) results in substantial inflammatory microglial reactivity and metabolic impairments in the brain, similar to those observed in disease mouse models. Furthermore, numerous publications from our lab have emphasized the importance of microglial reactivity in influencing neuronal damage and brain atrophy using the P301S mouse model of tauopathy. This is exemplified by the dramatic reduction in neuroinflammation and tau-mediated neurodegeneration in mice lacking expression of triggering receptor expressed on myeloid cells type 2 (TREM2), a gene selectively expressed in microglia in the brain. This led me to hypothesize that changes in sleep could epigenetically alter microglial responses to intraneuronal tau aggregates, thereby directly influencing the progression to neurodegeneration. To address this hypothesis, I used P301S mice lacking TREM2 or expressing the AD-associated R47H variant, or the common variant as a genetic means to identify distinct microglial responses influenced by SD. My preliminary data showed that chronic SD during early life followed by sleep recovery was neuroprotective and reduced TREM2-dependent microglial reactivity. This finding raises the intriguing possibility that sleep architecture can be re-trained to potentiate long-term transcriptional changes in microglia, reducing inflammatory damage and ultimately promoting neuroprotection by acting as an ‘epigenetic memory’ that determine disease outcomes. I will test this hypothesis in Aim 1. My pilot study also revealed that SD after onset of pathological tau overrides the neuroprotective effects of lack of TREM2 in P301S mice, leading to increased microglial reactivity and brain atrophy. This suggests that SD has the potential to exacerbate neuronal damage by epigenetically overriding the homeostatic restrictions on persistent inflammatory cascades typically maintained by the absence of TREM2 signaling in microglia. I will address this hypothesis in Aim 2. These aims will investigate the mechanistic impact of sleep on genetic regulatory processes within microglia, revealing its functional consequences in the context of tau-mediated neurodegeneration. A K99/R00 Award will provide me the opportunity to be trained in chromatin and methylation profiling as well as enhance my expertise in sleep and neurodegeneration research in the Wang and Holtzman labs at Washington University. These experiences will build the foundation of my future independent research in sleep and epigenetic mechanisms in neurodegenerative diseases.


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 = $124,797 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	2	6/25/2026	NON-COMPETING CONTINUATION	$124,797
														Subtotal = $124,797

Issue Date FY: 2025 ( Subtotal = $125,000 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	1	9/15/2025	NEW	$125,000
														Subtotal = $125,000

Grand Total All Awards = $249,797

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Epigenetic modulations by sleep to mitigate neurodegeneration

Award Number: K99AG090693

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/15/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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