Alzheimer's disease (AD) is a devastating neurodegenerative disorder for which no disease modifying treatment exists. Inheritance of the apolipoprotein E (APOE) ε4 allele strongly increases the risk of developing the sporadic form of AD, whereas the ε2 allele is protective. Though the precise role of the different APOE alleles remains unclear, in vitro and in vivo studies have demonstrated that each isoform differentially modulates the deposition, clearance, and degradation of amyloid-beta (Aβ) peptides that form the extracellular plaques of AD. Strategies directed toward increasing the levels of APOE2 could be useful in reducing plaques and alleviating disease progression. Additionally, advances in gene transfer using adeno-associated vectors (AAV) enable efficient and safe expression of therapeutic genes like APOE2. This dissertation, describes experiments that (1) test if intracerebroventricular gene delivery of APOE isoform can modulate amyloid pathology in transgenic animals that accumulate beta-amyloid, (2) evaluate the efficacy of a novel approach by intravenous infusion of AAV, and (3) characterize oligomeric Aβ (oAβ) in rhesus monkeys as a potential translational target.
Experiment 1 explored how each APOE isoform impacts the progression of AD pathology using intracerebroventricular injection of AAV4. This demonstrated isoform-dependent effects on Aβ-related neuropathology using multi-photon imaging, in vivo microdialysis, post-mortem immunohistochemistry, and array tomography.
Experiment 2 demonstrated the efficacy of intravenous delivery of AAV9 and increased efficiency of self-complementary AAV9 vectors compared to single-stranded AAV9. Furthermore, expression of transgene was restricted to CNS astrocytes by utilizing a restrictive promoter.
Finally, the presence of oAβ in rhesus macaque monkeys and its possible association with age-related cognitive decline was explored using fresh samples of monkey cortex. Soluble oAβ was detected in multiple cortical areas but was not significantly associated with age. Nevertheless, a significant positive correlation was observed between oAβ in frontal pole cortex and impairment on a behavioral test of executive function.
Taken together, these data suggest that gene transfer of APOEε2 may be useful for modulation APOE expression and beta-amyloid accumulations for the treatment of AD. Furthermore, the rhesus monkey may serve as a model system for future preclinical studies.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/15275 |
| Date | 12 March 2016 |
| Creators | Dashkoff, Jonathan |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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