ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid- beta 1-42

Amyloid- beta 1-42 (A beta 1-42) is crucial to Alzheimer disease (AD) pathogenesis but the conformation of the toxic A beta 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 A beta 1-42 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 A beta 1-42 did not affect LTP. These data provide a novel link among apoE isoform, A beta 1-42, and a functional cellular model of memory. In this model, apoE4 confers a gain of negative function synergistic with A beta 1-42, apoE2 is protective, and the apoE-A beta interaction is specific to oligomeric A beta 1-42.