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Nemo-like kinase regulation of microglial function and heterogeneity in Alzheimer's disease

Award Number: F31AG086008
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Nemo-like kinase regulation of microglial function and heterogeneity in Alzheimer's disease - Alzheimer’s disease (AD) is pathologically characterized by the accumulation of extracellular amyloid beta (Aβ) plaques, tau tangles, neuroimmune activation, and synaptotoxicity. Recent immunotherapies have focused on oligomeric and fibrillar Aβ species to slow or halt symptom progression with limited success, and this remains an active space for therapeutic development. Activation of microglial phagocytosis presents a promising strategy to utilize an intrinsic protein quality-control mechanism to counteract the hallmark protein aggregation in AD. Additionally, a disease-associated microglia (DAM) subpopulation appears in response to AD and several different neurodegenerative diseases, and accelerating DAM appearance could successfully counteract Aβ plaque pathology. However, the underlying signaling mechanisms and regulatory checkpoints promoting DAM activation are still not completely understood. Depletion of Nemo-like kinase (Nlk) in mice is strongly associated with increased lysosomal and phagocytic activity, but the implications of increasing these pathways in microglia in an AD context has yet to be examined. Additionally, knockout of Nlk successfully ameliorates both protein aggregation and behavioral deficits in a murine TDP43-associated proteinopathy model. This Nlk deletion also induces the expression lysosomal and phagocytic genes that are also upregulated in the homeostatic microglia to DAM transition. Given this rationale, the central hypothesis of this proposal is that depletion of microglial Nlk in a murine model of AD will increase phagocytic degradation of Aβ, significantly improve AD phenotypes, and induce microglia differentiation from a homeostatic state to DAM. Therefore, this proposal aims to measure AD symptom progression using (1) histopathological markers of disease etiology and (2) behavioral paradigms assessing cognition and working memory. Biochemical and histological analyses will identify the effect of Nlk loss on Aβ plaque formation, levels of soluble Aβ oligomers and fibrils, microgliosis, and synapse loss. Separately, single-cell RNA sequencing (scRNAseq) will assess a conditional Nlk knockout produces transcriptional changes required for the DAM transition. If the hypothesis is supported, activation of microglia could present a holistic strategy for counteracting the characteristic protein aggregation in neurodegenerative proteinopathies. This proposed project will be completed in Dr. Janghoo Lim’s lab in the Yale Departments of Neuroscience and Department of Genetics. This unique environment will provide the skills and training in both scRNAseq pipelines and neuro-immune interactions required to successfully complete these aims. The overall environment at Yale University and within the Yale Interdepartmental Neuroscience Program also provides opportunities to develop scientific communication and mentoring skills. The proposed fellowship training will prepare the applicant to be a successful independent researcher studying the role of glia and neuro-immune interactions in the context of neurodegeneration.


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 = $35,120 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	000	3	2/26/2026	NON-COMPETING CONTINUATION	$34,544
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	001	3	3/24/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $35,120

Issue Date FY: 2025 ( Subtotal = $34,514 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	000	2	8/21/2025	NON-COMPETING CONTINUATION	$34,514
														Subtotal = $34,514

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	000	1	12/6/2023	NEW	$47,694
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	001	1	4/30/2024	NEW	$1,280
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Aging Research	002	1	4/30/2024	NEW	$0
														Subtotal = $48,974

Grand Total All Awards = $118,608

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Nemo-like kinase regulation of microglial function and heterogeneity in Alzheimer's disease

Award Number: F31AG086008

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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