Lipidated ApoE is found in nanoscale proximity to Aβ aggregates in human Alzheimer brains.

Apolipoprotein E ( APOE ) associates with amyloid plaques (Aβ) in Alzheimer disease (AD). The ε4 allele of apolipoprotein E ( APOE ε4) is the strongest genetic risk factor for sporadic AD and exacerbates Aβ plaque burden relative to APOE ε3 and APOE ε2. The majority of ApoE associates with multiple lipid classes to form lipoproteins both in the brain and the periphery. However, the lipidation status of Aβ plaque-associated ApoE is not yet fully defined. Here, we use fluorescence lifetime imaging microscopy coupled with Förster resonance energy transfer (FLIM-FRET) to determine the lipidation status of ApoE in plaques, as well as the nanoscale spatial proximity of ApoE and Aβ to anionic lipids and cholesterol within human AD brain tissue. We demonstrate that lipids are in close nanoscale proximity to ApoE and Aβ within Aβ plaques. Our results reveal that lipidated ApoE complexes enriched in anionic lipids and cholesterol are core constituents of AD plaques in-situ . We propose a pathological mechanism in which the surface presentation of anionic lipids on ApoE lipoproteins facilitates initial interaction with and subsequent aggregation of Aβ.