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Dysfunction of microglial proteostasis drives neuroinflammation and cognitive decline following pneumonia

Award Number: F31AG071225
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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Dysfunction of microglial proteostasis drives neuroinflammation and cognitive decline following pneumonia - PROPOSAL SUMMARY / ABSTRACT Multiple lines of clinical evidence demonstrate a link between pneumonia, cognitive impairment, and dementia in the elderly. The mechanisms underlying this susceptibility, however, remain unclear. In this proposal, we will test the hypothesis that loss of proteostasis in old microglia results in a persistent maladaptive response to immune insult that precludes recovery of neuronal plasticity and cognitive capacity after severe viral pneumonia. Toward this aim, the Budinger/Misharin Laboratory has developed a murine model of pneumonia using influenza A virus, which we will use to compare cognitive recovery in young and old animals and models of Alzheimer's disease (AD). Our preliminary transcriptomics data from bulk brain tissue and flow-sorted microglia suggests that microglia in old animals develop significant proteostasis dysfunction, and adopt a pro- inflammatory phenotype in the steady state. This is exacerbated by persistent activation of the integrated stress response after pneumonia, in addition to aberrant increases in antigen presentation and gliogenic markers. We hypothesize that microglial proteostasis deficits in aging and in AD may impair homeostatic function and “prime” an aberrant response to infection, leading to neurodegeneration and cognitive impairment after insult. In this proposal, we will first test whether microglia are necessary for the initiation of cognitive impairment in murine models of aging and AD, using pharmacological ablation. We will then determine whether cognitive deficits after pneumonia in aging and AD can be rescued through inhibition of the ISR with the small- molecule inhibitor ISRIB. Finally, we will determine whether activation of the ISR in microglia, alone, is necessary or sufficient for the precipitation of cognitive impairment in AD using genetic manipulation of the ISR effector Atf4. This study will help to critically evaluate the role of infection in the development of sporadic dementia, and may aid in the development of prophylactic therapies for age-related cognitive impairment.


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 = -$28,480 )
2025	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	3	6/25/2025	NON-COMPETING CONTINUATION	-$28,480
														Subtotal = -$28,480

Issue Date FY: 2023 ( Subtotal = $43,590 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	3	12/7/2022	NON-COMPETING CONTINUATION	$42,648
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	001	3	2/23/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $43,590

Issue Date FY: 2022 ( Subtotal = $42,301 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	002	2	7/26/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	001	2	5/3/2022	NON-COMPETING CONTINUATION	$717
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	2	12/27/2021	NON-COMPETING CONTINUATION	$41,585
														Subtotal = $42,301

Issue Date FY: 2021 ( Subtotal = $41,249 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	001	1	2/5/2021	NEW	$0
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	002	1	3/10/2021	NEW	$516
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	1	1/14/2021	NEW	$40,733
														Subtotal = $41,249

Grand Total All Awards = $98,660

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Dysfunction of microglial proteostasis drives neuroinflammation and cognitive decline following pneumonia

Award Number: F31AG071225

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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