Project Details
Description
PROJECT SUMMARY (APOE U19: Project 3)
Apolipoprotein E (apoE) is a major genetic determinant of late-onset Alzheimer’s disease (AD) with APOE4
increases the risk and APOE2 being protective compared with common APOE3 allele. Our team-based work
will investigate a novel ApoE Cascade Hypothesis (ACH) which will shed light on the disease mechanisms and
inform future therapeutic strategies for AD. Here, Project 3 seeks to elucidate whether different isoforms of
astrocytic and microglial apoE exhibit different biochemical properties that impact its function, aggregation, and
the metabolism of amyloid-β (Aβ) during aging and AD development. In addition to astrocytes, microglia
secrete abundant lipidated apoE with aging and in the context of AD pathogenesis. The disease-associated
microglia (DAM) exhibit a conserved transcriptional signature across different AD mouse models with APOE
being one of the central hub genes. Interestingly, activated microglia have been shown to induce neurotoxic
(A1-like) reactive astrocytes in AD. However, little is known about whether apoE isoform-mediated microglia-
astrocyte interaction affects brain functions and amyloid pathologies. To address these questions, we have
generated novel inducible mouse models in which human APOE2, APOE3, or APOE4 gene is specifically
expressed in astrocytes or microglia. In Aim 1, we will analyze the effects of astrocytic or microglial apoE
isoforms on cognitive function, lipid metabolism, neuroinflammation, and vascular integrity during aging. In Aim
2, we will define the impacts of astrocytic or microglial apoE isoforms on brain function, neuroinflammation, and
the development of amyloid pathology. In Aim 3, we will determine the role of apoE isoforms in astrocyte-
microglia interaction and their association with cerebrovasculature during aging and in the context of amyloid
pathology. Using unique mouse models and innovative technologies (ie., in vivo 2-photon imaging and in vivo
microdialysis), we will comprehensively investigate how apoE isoforms in glia cells contribute to brain cognition
and amyloid pathology. More importantly, multi-disciplinary approaches will be employed by interacting with
other projects/cores: 1) The properties of apoE particles from our mouse models will be analyzed by Project 1
and Core B; 2) ApoE amounts and AD-related fluid biomarkers will be measured through Core D; 3) The
amyloid pathologies and neuroninflammation will be examined by Core C; 4) The molecular phenotypes of our
inducible apoE mouse models will be examined using multi-omics approaches (ie., proteomics, metabolomics,
lipidomics and single cell RNA sequencing), with results correlating with human studies through Cores F, G; 5)
Our data can be compared with studies from Projects 2 and 4 to further elucidate the cell type-specific effects;
and 6) Findings from mouse models can be further validated using human iPSC-derived microglia/astrocyte
models in Core E. Through multidisciplinary team with synergized expertise and resources, we will
collaboratively understand the apoE-associated disease mechanisms in aging-related conditions and AD.
Status | Active |
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Effective start/end date | 2/1/21 → 5/31/24 |
Funding
- National Institute on Aging: $550,250.00
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