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Influence of thalamic IL-33 signaling in aging-associated exacerbation of cognitive impairment after brain injury via microglial dysfunction and tau pathology

Award Number: R01AG079129
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Influence of thalamic IL-33 signaling in aging-associated exacerbation of cognitive impairment after brain injury via microglial dysfunction and tau pathology - ABSTRACT Traumatic brain injury is a risk factor for cognitive impairment and dementia, such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), particularly in the aged populations. Nevertheless, the mechanisms by which aging exacerbates cognitive deficits after brain injury are not fully understood. Human brain imaging studies reported the signs of microglial activation in the thalamus that correlate with cognitive deficits. Our preliminary studies using a local microglia depletion in mice have discovered that thalamic microglia activation is required for cognitive deficits after brain injury. In the middle-aged mice, cognitive deficits after brain injury were exacerbated and accompanied by dysregulated responses of microglia and accumulation of AT8-positive phosphorylated tau proteins (p-tau). Recent studies have reported that one of the aging-associated molecular signatures in the mouse brain is an increased interleukin-33 (IL-33) expression in oligodendrocytes. Indeed, IL- 33 expression was increased in thalamic oligodendrocytes. Notably, blocking of IL-33 in the aging thalamus ameliorated aging-associated exacerbation of cognitive deficits. These findings suggest that aging-associated changes in the thalamic environment and microglial responses contribute to p-tau accumulation and exacerbated cognitive deficits in aged mice after cortical injuries. Thus, in the proposed study, we will test our hypothesis that aging-associated oligodendrocyte-derived IL-33 exacerbates cognitive impairment after cortical injury by driving microglial dysfunction and tau pathology in the thalamus. In Aim 1, we will further evaluate aging-associated changes in thalamic pathology and cognitive impairment after cortical injuries and determine the effects of thalamic microglial depletion and neuronal tau deletion on exacerbated cognitive impairment. In Aim 2, we will investigate the requirement of oligodendrocyte-microglial IL-33 signaling in aging-associated microglial dysfunction, p-tau accumulation, and worsening cognitive impairment after cortical injuries. In Aim 3, we will examine the mechanisms by which aging-associated IL-33 signaling alters microglial responses after cortical injuries. Together, this study will determine the mechanisms by which oligodendrocyte-microglia IL-33 signaling induces microglial dysfunction, p-tau accumulation, and cognitive impairment relevant for AD/ADRD.


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 = $459,561 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	3	7/14/2026	NON-COMPETING CONTINUATION	$459,561
														Subtotal = $459,561

Issue Date FY: 2025 ( Subtotal = $445,757 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	2	8/19/2025	EXTENSION WITH OR WITHOUT FUNDS	$445,757
														Subtotal = $445,757

Grand Total All Awards = $905,318

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Influence of thalamic IL-33 signaling in aging-associated exacerbation of cognitive impairment after brain injury via microglial dysfunction and tau pathology

Award Number: R01AG079129

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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