APOE Genotype Results in Differential Effects on the Peripheral Clearance of Amyloid-β42 in APOE Knock-in and Knock-out Mice

Abstract

The ε4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer’s disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-β (Aβ) is rapidly removed from the plasma by the liver and kidney and that the rate of its clearance is affected by ApoE in C57BL/6J and APOE−/− mice. To expand upon these findings, we assessed the peripheral clearance of human synthetic Aβ42 in APOE ε2, ε3, and ε4 knock-in and APOE knock-out mice injected with lipidated recombinant apoE2, E3, and E4 protein. Our results show that APOE does influence the rate at which the mice are able to clear Aβ42 from their bloodstream. Both APOE ε4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Aβ42 over time compared to APOE ε2/APOE knock-out rE2 and APOE ε3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Aβ42 is significantly altered by APOE genotype. Given that APOE ε4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of Aβ which may impact on clearance from the brain.

Low Plasma ApoE Levels Are Associated with Smaller Hippocampal Size in the Alzheimer's Disease Neuroimaging Initiative Cohort

“…This mechanism might be expected to be more relevant to ApoE levels in the brain than in the plasma, but previous work with transgenic APOE mice indicates that APOE genotype has similar effects on brain and plasma ApoE levels [15]. Although ApoE does not appear to cross the blood-brain barrier [40], ApoE levels and isoforms modulate Aβ clearance from the plasma [41], which may in turn affect Aβ clearance from the brain.…”

Age-associated evolution of plasmatic amyloid in mouse lemur primates: relationship with intracellular amyloid deposition

“…In small animals, Aβ can be measured more easily in the plasma. These measurements are used to evaluate the effects of various biological factors such as APOE genotype on Aβ clearance (Sharman et al, 2010) or to assess therapeutic effects of potential drugs. For example, studies in transgenic mouse models of AD have shown that treatments with γ- or β-secretase inhibitors reduce plasmatic Aβ 42 and Aβ 40 (Chang et al, 2004; Kounnas et al, 2010; Lanz et al, 2010).…”

Targeting ApoE4/ApoE receptor LRP1 in Alzheimer's disease

“…However, Sharman et al [86] have shown that ApoE influences the rate of hepatic Ab 42 uptake in mice in an isoform-specific manner. Both human ApoE4 knockin mice and ApoE knockout mice injected with lipidated recombinant ApoE4 protein showed significantly longer Ab 42 plasma retention time compared to ApoE2 or E3 knockin mice and mice injected with lipidated recombinant ApoE2 or E3, respectively [86]. This is consistent with the findings showing an ApoE isoform-specific disruption of Ab clearance at the BBB [19].…”