Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE

Molecular mechanisms underlying Apo-E isoform-dependent risk and the relevance of ApoE-associated lipids in Alzheimer’s disease remain elusive.

ApoE2 and ApoE Christchurch variants are defective in LDLR binding, thus reducing the uptake of ApoE and associated lipid cargoes.

LDLR-mediated internalization and endolysosomal delivery of ApoE lipoprotein particles carrying cholesterol esterified with polyunsaturated fatty acids result in lipofuscin deposition with the allelic series ApoE2 < ApoE3 < ApoE4.

Lipofuscin increased lysosomal accumulation of tau fibrils and was elevated in the APOE4 mouse brain with exacerbation by tau pathology. Intrahippocampal injection of PUFA-CE-lipApoE4 was sufficient to induce lipofuscinosis in wild-type mice.

https://www.cell.com/cell/fulltext/S0092-8674(24)01209-1

https://sciencemission.com/Decreased-lipidated-ApoE-receptor-interactions