Mechanisms of ApoEIsoform Effects in Alzheimer’s Disease

Alzheimer’s disease (AD) is the primary cause of dementia in the elderly. Mutations that increase the 42 amino acid form of the peptide amyloid-beta (Aβ42) is the only known cause of AD, but accounts for less than 5% of AD cases. Currently, disease-modifying therapies aimed at decreasing Aβ levels in the brain have yielded no successful results. The ε4 allele of apolipoprotein E (apoE) is a major risk factor for AD. Of the three apoE isoforms, apoE4 increases AD risk 4-15 fold while apoE2 decreases AD risk 2-4 fold, compared to apoE3. While the mechanism remains elusive, apoE isoforms and Aβ may interact in a manner that leads to or prevents AD pathogenesis. ApoE plays critical roles in the regulation of lipid and cholesterol homeostasis; synapse development, function and repair; and anti-inflammatory responses. ApoE also interacts directly with Aβ to modulate its toxicity, clearance and deposition in the brain. This thesis examined the effects of apoE isoforms on synapses via analysis of changes in dendritic spines, and on the outcomes of apoE and Aβ interactions. ApoE is secreted primarily by glia. Therefore, glia isolated from apoE-targeted replacement mice that express apoE2, apoE3 or apoE4 in the place of mouse apoE were utilized in long-term neuron-glia co-cultures and glial cultures for analysis of apoE isoform effects on dendritic spines, and apoE and Aβ interactions, respectively. The current study shows that apoE isoforms differentially influence maintenance of spines during neuron maturation, where apoE4 delays spine formation and enhances loss of mature spines, while apoE2 enhances formation and maintenance of mature spines, relative to apoE3. Analysis of apoE and Aβ interactions show that clearance of soluble Aβ oligomers, the main toxic Aβ species, is impaired in apoE4. In addition, Aβ affects apoE level and solubility. Both Aβ clearance and deposition decreased the level of soluble apoE – an effect that could have pronounced negative effects on the various neuroprotective functions of apoE. Altogether, results from this study suggest that therapeutic interventions aimed at not only Aβ clearance, but also replenishment of apoE and restoration of synapse integrity may provide a more successful AD therapy.