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Elucidating the Cell-Type Specific Neuroprotective Mechanisms in the APOE3 Christchurch Mutation in Alzheimer's Disease

Award Number: F32AG085960
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2026
AWARD TERMINATION DATE: 05/29/2025

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Elucidating the Cell-Type Specific Neuroprotective Mechanisms in the APOE3 Christchurch Mutation in Alzheimer's Disease - PROJECT SUMMARY Alzheimer’s Disease (AD) is the most prevalent form of late-onset dementia, known for the presence of amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau. There is a portion of patients with AD who develop symptoms before the age of 65, known as early-onset autosomal dominant AD (ADAD), caused by mutations in the presenilin-1 (PSEN1) gene. A specific kindred of these patients was identified for having PSEN1 E280A mutations in Colombia, leading to mild cognitive impairment in their early 40s and dementia by late 40s. One patient from this kindred interestingly did not develop any memory deficits until she was in her 70s. Postmortem analyses showed that in addition to her PSEN1 E280A mutation, she also was homozygous for a mutation in her APOE3 gene, known as the Christchurch mutation (APOE3cc). Apolipoprotein E (APOE) is a lipid transporter that is expressed by astrocytes and microglia in the central nervous system and is the most common risk factor for AD. Ultimately, a better understanding of how this mutation yields resilience against ADAD could be a promising therapeutic target for AD. First, we created a mouse model of human APOE3cc to replicate the patient’s rare homozygous mutation in mice. We leveraged single nuclei RNA sequencing (snRNAseq) to elucidate which cell types could be responsible for APOE3cc’s resilience. The snRNAseq data implicated both microglia and astrocytes as regulators of APOE3cc’s neuroprotection. In microglia, our data showed that ApoEcc/cc+P301S mice significantly downregulated several interferon genes. High levels of type-I interferons in the CNS, present in both aging and neurodegeneration, have been associated with detrimental effects on cognition. In astrocytes, ApoEcc/cc+P301S mice showed reprogramming of mitochondrial and antioxidant genes. Oxidative stress and neurodegeneration are inextricably linked, and having increased antioxidant genes could explain downstream resiliency in the patient. Additionally, previous studies have linked oxidative stress to activation of the interferon pathway. I hypothesize that the combination of microglial interferon suppression and astrocytic antioxidant reprogramming protect against tau-mediated dysfunction in the ApoE3cc/cc mice. To test this hypothesis, we aim to determine the following: 1) determine the relationship of the interferon response in ApoE3cc/cc microglia to neuronal health and neurite outgrowth. 2) analyze the ApoE3cc/cc astrocytic mitochondrial, antioxidant, and metabolic response to tauopathy. Both aims will utilize a combined in vivo and in vitro approach.


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 = $43,610 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	002	3	3/25/2026	NON-COMPETING CONTINUATION	$1,308
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	001	3	2/10/2026	NON-COMPETING CONTINUATION	$80,740
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	003	3	8/7/2026	TERMINATION	-$39,674
2026	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	000	2	1/12/2026	OTHER REVISION	$1,236
														Subtotal = $43,610

Issue Date FY: 2025 ( Subtotal = $76,984 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	001	2	5/29/2025	TERMINATION	$0
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	000	2	11/15/2024	NON-COMPETING CONTINUATION	$76,984
														Subtotal = $76,984

Issue Date FY: 2024 ( Subtotal = $76,528 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	002	1	4/30/2024	NEW	$4,748
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	1	11/17/2023	NEW	$71,780
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	001	1	11/17/2023	NEW	$0
														Subtotal = $76,528

Grand Total All Awards = $197,122

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Elucidating the Cell-Type Specific Neuroprotective Mechanisms in the APOE3 Christchurch Mutation in Alzheimer's Disease

Award Number: F32AG085960

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2026

AWARD TERMINATION DATE: 05/29/2025

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