Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways

The increased risk of Alzheimer's disease (AD) associated with specific apolipoprotein E (ApoE) isoforms appears to relate to altered amyloid-β (Aβ) homeostasis. Clearance of Aβ from the brain is reduced in the presence of the AD-associated ApoE4 isoform, which may contribute to the accumulation of Aβ deposits in the parenchyma and vasculature. The low-density lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans (HSPGs), both established ApoE receptors, are involved in Aβ uptake, with LRP1 additionally implicated in Aβ transcytosis across the blood-brain barrier. In this study, we detected the co-distribution of heparan sulfate (HS), ApoE and LRP1 in Aβ(1-40)-positive brain microvessels from individuals with Down's syndrome diagnosed with AD. In addition, ApoE was pulled-down from AD cerebrospinal fluid with anti-Aβ antibodies. Using Chinese hamster ovary cells deficient in HS or LRP1, we found that ApoE increases cell association of Aβ in a HSPG- and LRP1-dependent manner; and further, ApoE processing is altered in the absence of cellular HS. These interactions may facilitate Aβ clearance from the brain, but if overwhelmed could contribute to Aβ accumulation and the pathogenesis of AD.