Insoluble α-synuclein in Alzheimer's disease without Lewy body formation

Insoluble α-synuclein plays a central role in Lewy body diseases, with considerable controversy as to whether it plays a similar role in Alzheimer's disease (AD). We assessed the tissue location and solubility of cortical α-synuclein in AD (without Lewy body formation) compared with controls, using sequential extraction procedures and Western immunoblotting to quantify different α-synuclein species in their different solubility states. Controls had no insoluble cortical α-synuclein and a ratio of soluble:lipid-associated α-synuclein 1.2 ± 0.1. Total α-synuclein protein was significantly increased in AD and concentrated within the lipid-associated fraction (soluble:lipid ratio 0.9 ± 0.05, soluble:insoluble 1.5 ± 0.1, lipid:insoluble 1.7 ± 0.1) which proved difficult to localize in paraffin-embedded tissue. Tissues prepared without lipid extraction revealed α-synuclein-immunoreactivity in the amorphous components of mature cored AD plaques. This lipid-association of the α-synuclein in mature AD plaques links this protein with other lipid changes thought to be important in disease pathogenesis