ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-β1-42

Amyloid-β1-42 (Aβ1-42) is crucial to Alzheimer disease (AD) pathogenesis but the conformation of the toxic Aβ species remains uncertain. AD risk is increased by apolipoprotein E4 (apoE4) and decreased by apoE2 compared with the apoE3 isoform, but whether inheritance of apoE4 represents a gain of negative or a loss of protective function is also unresolved. Using hippocampal slices from apoE knockout (apoE-KO) and human apoE2, E3, and E4 targeted replacement (apoE-TR) mice, we found that oligomeric Aβ1-42 inhibited long-term potentiation (LTP) with a hierarchy of susceptibility mirroring clinical AD risk (apoE4-TR > apoE3-TR = apoE-KO > apoE2-TR), and that comparable doses of unaggregated Aβ1-42 did not affect LTP. These data provide a novel link among apoE isoform, Aβ1-42, and a functional cellular model of memory. In this model, apoE4 confers a gain of negative function synergistic with Aβ1-42, apoE2 is protective, and the apoE-Aβ interaction is specific to oligomeric Aβ1-42.