Grants and Contracts Details
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.
|Effective start/end date||12/1/22 → 11/30/27|
- National Institute on Aging: $642,417.00
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.