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Role of apoE-mediated meningeal lymphatic remodeling in the pathophysiology of Alzheimer’s disease

Award Number: R01AG080556
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Role of apoE-mediated meningeal lymphatic remodeling in the pathophysiology of Alzheimer’s disease - ABSTRACT Aging and expression of apolipoprotein E ε4 (APOE4) gene alleles represent two major risk factors for Alzheimer’s disease. Recent studies have shown that aging leads to impaired brain fluid drainage by the bona fide lymphatic vascular network that is found in the mammalian meningeal dura. Interestingly, early loss of meningeal lymphatic drainage has been linked to worse amyloid-β (Aβ) pathology, vascular and microglial activation, and spatial memory deficits in Alzheimer’s disease mouse models of brain amyloidosis. However, little is known about the effects of APOE4 expression on meningeal lymphatic function. Our preliminary data shows that expression of APOE4 in humanized knock-in mice leads to a deleterious remodeling of meningeal lymphatic vessels and reduced drainage of cerebrospinal fluid (CSF) into the cervical lymph nodes. Interestingly, we also show that meningeal peri-lymphatic myeloid cells are a main local source of apoE protein and become activated in middle-aged APOE4 mice. These observations led us to raise the overarching hypothesis that expression of APOE4 disturbs the crosstalk between meningeal innate myeloid and lymphatic endothelial cells, which will subsequently lead to reduced CSF drainage by meningeal lymphatics, and exacerbated neuroinflammation and brain amyloidosis in Alzheimer’s disease. In Aim 1, we plan to use constitutive or conditional knockout mouse models to investigate the cell autonomous and non-autonomous effects of APOE4 on meningeal lymphatic dysfunction at different ages, determine the underlying innate immune transcriptional signatures, and identify alterations in lymphatic growth factors and/or cytokines. In Aim 2, we will test the hypothesis that an early impairment in meningeal lymphatic drainage promotes a faster cognitive decay in APOE4 mice, and that fine-tuning meningeal lymphatics in aged APOE4 mice ameliorates neuronal function and cognition in sex-dependent manner. To assess this, will modulate meningeal lymphatic drainage, using adeno- associated viruses that promote lymphatic vessel ablation or expansion, and evaluate the downstream effects on the neuronal transcriptomes, synaptic plasticity, and behavioral performances of aged female and male APOE humanized mice. In Aim 3, the therapeutic outcomes of manipulating meningeal lymphatic function will be tested in a knock-in Alzheimer’s disease mouse model of brain amyloidosis, the APP-SAA, expressing APOE3 or APOE4. After inducing meningeal lymphatic vessel loss or expansion in 2- and 10-month-old mice, we will evaluate different experimental outcomes including behavioral performance, neuronal activity, brain interstitial fluid Aβ (by in vivo microdialysis), soluble and insoluble Aβ aggregates, and the profiles of innate and adaptive immune cell activation in the brain and its border tissues. Altogether, this proposal will allow us to uncover novel mechanisms of meningeal lymphatic decline that will serve as cornerstones for future projects and might lead to novel therapies to treat APOE4 allele carriers that are at a greater risk of developing Alzheimer’s disease.


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 = $767,846 )
2026	2026	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	000	2	8/11/2026	EXTENSION WITH OR WITHOUT FUNDS	$767,846
														Subtotal = $767,846

Grand Total All Awards = $767,846

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Role of apoE-mediated meningeal lymphatic remodeling in the pathophysiology of Alzheimer’s disease

Award Number: R01AG080556

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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