Apolipoprotein E4 is the strongest risk factor for late-onset Alzheimer’s Disease (AD) while apoE3, the common isoform, is neutral with respect to this disease. The only difference between the isoforms is a single amino acid change with an arginine residue at position 112 in apoE4 but a cysteine at this position in apoE3. In order to investigate how this single amino acid change exerts such a strong effect on the outcome of AD we have examined the apoE isoforms with respect to their structural properties, self-association and lipid-binding behavior and their interactions with Aβ. We find that self-association and lipid-binding behavior do not differ significantly between the apoE isoforms consistent with our structural data that show that regions of structural differences between the apoE isoforms are close to but not overlapping with the self-association or lipid-binding regions. However, interaction of apoE with Aβ oligomers is strongly apoE isoform dependent with the strongest effects for apoE4. Our data indicate that apoE4 exerts its pathological influence in AD by stabilizing the toxic oligomers of Aβ. We are now using the information obtained from our biophysical measurements to develop small molecules to target apoE4 to ameliorate its pathogenic properties in AD.
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