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Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids

Award Number: R01AG079223
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids - PROJECT SUMMARY Neuroinflammation and innate immune response have emerged as the forefront pathology of Alzheimer’s disease (AD). Accumulated evidence has shown that Apolipoprotein E4 (APOE4), the most significant AD genetic risk factor, confers a pro-inflammatory state in the normal aging and AD brains. However, most studies have centered around the roles of APOE4 in disrupting the homeostatic functions of astrocytes and microglia in brain parenchyma. Recent discoveries of a lymphatic system in the dura meninges and a repertoire of immune cells at brain borders have highlighted the critical role of border immunity in brain aging and AD. APOE is highly expressed in the border-associated macrophages (BAMs), dura lymphatic vessels, and choroid plexus. Thus, those studies raise a critical question on whether APOE4 regulates the border-associated immunity in normal aging and AD. Despite the recent single-cell transcriptomic study on mouse BAMs18, little information exists on cell states of human brain borders related to normal aging and AD, neither the APOE4’s effects on border cell states, immunity, and functions. The overall goal of this application is to investigate the effect of APOE alleles on cell states and functions of human brain borders in normal aging and AD. Our central hypothesis is that AD and APOE4 alter cell states in brain border regions, and APOE4 exacerbates molecular and cellular phenotypes in control and AD isogenic border cell models. We formulated this hypothesis based on literature as mentioned above and our transcriptomic analysis showing distinct cell transcriptomic signature and strong APOE expression in BAMs at human brain borders. We will test this hypothesis by combining single-cell multi-omics profiling of ex vivo human border regions and in vitro border region modeling. Specifically, we will first profile the single-cell transcriptome and chromatin accessibility from the same cells of postmortem meninges and choroid plexus of APOE4 and non-APOE4 carriers from control and AD individuals. This Aim will enable us to reveal cell types, cell states, regional specificity, and intercellular communications at human brain borders and identify upstream master regulators of AD- and APOE4-specific cell states (Aim 1). To study the APOE4’s functions in human brain borders, we will develop multicellular choroid plexus 3D models by introducing iPSC-derived immune cells to choroid plexus organoids. We will then generate control and AD isogenic choroid plexus models carrying either APOE3 or APOE4 alleles to examine the APOE4’s cellular, molecular, and functional effects in both cell-autonomous and non-cell-autonomous manners (Aim 2). Our study will shed significant insights into human border-associated immunity and reveal a novel mechanism underlying AD pathophysiology. The upstream regulators of AD- and APOE4-specific cell states identified in this study will serve as ideal therapeutic targets for modulating the brain border immunity. Our choroid plexus model provides a tractable system to test other genetic targets, extrinsic factors, and candidate drugs, opening a new avenue of targeting the brain borders for AD therapeutic interventions.


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 = $706,933 )
2026	2026	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	000	5	5/28/2026	NON-COMPETING CONTINUATION	$706,933
														Subtotal = $706,933

Issue Date FY: 2025 ( Subtotal = $716,020 )
2025	2025	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	000	4	8/18/2025	NON-COMPETING CONTINUATION	$716,020
														Subtotal = $716,020

Issue Date FY: 2024 ( Subtotal = $730,633 )
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	000	3	5/21/2024	NON-COMPETING CONTINUATION	$730,633
														Subtotal = $730,633

Issue Date FY: 2023 ( Subtotal = $754,333 )
2023	2023	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	000	2	5/25/2023	NON-COMPETING CONTINUATION	$754,333
														Subtotal = $754,333

Issue Date FY: 2022 ( Subtotal = $785,933 )
2022	2022	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Aging Research	000	1	8/22/2022	NEW	$785,933
														Subtotal = $785,933

Grand Total All Awards = $3,693,852

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Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids

Award Number: R01AG079223

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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