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Description
Abstract
The polymorphic gene Apolipoprotein E (APOE) has three common alleles that convey
dramatically different risk for late onset Alzheimer’s disease (E2, E3, and E4). In comparison to
the highly protective E2 allele, E4 has been associated with a host of detrimental effects,
including, but not limited to, more severe AD neuropathology, increased neuroinflammation and
metabolic and cerebrovascular deficits. With its strong risk profile and varied biological
mechanisms, APOE has emerged as an attractive candidate for gene therapy. In addition to
providing a much-needed preclinical model for ongoing and future trials, exploration of E4 to E2
allele ‘switching’ has the potential to help answer several fundamental and longstanding
biological questions in the field. For example, which ApoE-synthesizing cell-type(s) drives AD
pathogenesis in E4 carriers and which are most protective in those with E2? Are E4-associated
deficits set in stone at birth (developmentally), or is later-life APOE editing a feasible approach
to mitigate AD pathology and cognitive dysfunction? To this end, we have generated a novel
APOE ‘switch’ mouse model (4s2) that leverages the Cre-LoxP system to allow for temporal and
cell/organ specific allele switching from E4 to E2. Our preliminary data confirms that the 4s2
mice synthesize a full-length human ApoE4 at baseline, and importantly, when crossed to
inducible CreERT2 (Cre) strains, the switch successfully leads to efficient (>98%) recombination
and expression of human ApoE2 in cell types of interest. Given the remarkable protective
effects of E2 carriage and the various roles of ApoE at differing steps of AD pathogenesis, we
hypothesize that CNS cell-specific allelic switching to E2 will simultaneously rescue multiple
metabolic, immune and neuropathological deficits previously associated with E4. We propose to
leverage these unique mouse models to determine the therapeutic window for peripheral or
CNS-specific E4 to E2 allele switching to mitigate metabolic deficits, neuroinflammation, amyloid
pathology, and cognitive dysfunction. If successful, this proposal will provide an essential
preclinical model for ongoing and future clinical trials, and will provide critical new information
regarding ideal cell-, region- and temporally-specific opportunities for therapeutic ApoE
modulation.
Status | Active |
---|---|
Effective start/end date | 10/1/22 → 9/30/25 |
Funding
- Alzheimers Association: $546,570.00
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Projects
- 1 Active
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Replacement of Peripheral APOE4 with APOE2: Effects on AD Pathogenesis.
10/1/22 → 9/30/25
Project: Research project