Project Details
Description
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.
Status | Active |
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Effective start/end date | 9/1/23 → 8/31/26 |
Funding
- National Institute on Aging: $2,250,745.00
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