Amyloid beta (Aß) deposition is a hallmark pathology in Alzheimer’s disease (AD). The apolipoprotein E (ApoE) gene, which encodes for the ApoE protein, has been established as a strong influence for the development of late-onset AD(1). The link between ApoE and Aß is unclear. One theory postulates that ApoE directly binds with Aß to mediate Aß clearance(2-4), while a second theory suggests the effects of ApoE on Aß clearance are indirect(5-7). Recent papers by Carlo et al(8) and Verghese et al(9) support these two respective contradicting theories.
In line with the first theory of a direct interaction between ApoE and Aß, Carlo et al found that sortilin, and not low-density lipoprotein receptor-related protein 1 (LRP1), mediates the cellular uptake of Aß/ApoE complexes, suggesting that sortilin is a major ApoE receptor that is essential for Aß clearance(8). In contrast, Verghese et al demonstrated that ApoE and Aß rarely bind together and that ApoE competes with Aß to bind with LRP1(9), which plays a role in neuronal Aß uptake(10). Thus, Verghese et al’s results suggest that ApoE inhibits Aß clearance via binding to LRP1(9). Verghese et al’s findings therefore are in accordance with the second theory that ApoE indirectly affects Aß clearance.
It would appear as though the experiments done by Carlo et al and Verghese et al are in contradiction with each other. However, there are important differences between these studies that may contribute to their contrasting results. First, Carlo et al examined the effects of sortilin and LRP1 on Aß/ApoE complexes, while Verghese et al did not use Aß/ApoE complexes in their experiments with LRP1. This might indicate that LRP1 is capable of binding to Aß only when it is not bound to ApoE. While there is an overwhelming amount of evidence that shows a direct interaction between ApoE and Aß(11-16), which supports Carlo et al, Verghese et al pointed out that the majority of studies demonstrating Aß/ApoE binding used synthetically prepared Aß at above physiological concentrations and did not assess the mechanisms behind the effects of Aß/ApoE complexes on Aß metabolism9. Verghese et al challenges previous literature as they show that Aß and ApoE rarely bind together under physiological conditions yet ApoE continues to affect Aß clearance, suggesting that the primary role of ApoE in Aß clearance is unlikely due to ApoE sequestering Aß. This implies that the two groups examined different pathways of ApoE-related Aß clearance: one pathway that depends on Aß/ApoE complexes and one that does not. Thus, the results from the two groups do not necessarily oppose each other as they targeted different pathways that may both contribute to Aß clearance, but the question remains as to which pathway contributes the most to Aß clearance.
In order to reconcile the results from Carlo et al and Verghese et al, several experiments could be done. Aß uptake should be measured in sortilin-expressing, sortilin-deficient, LRP1-expressing, and LRP1- deficient cells incubated with soluble Aß only, soluble Aß with ApoE (with molar ratios in the physiological range, as previously described(9)), and Aß complexed with ApoE (as previously described(8)). This would enable us to determine how free ApoE and Aß-bound ApoE influence Aß clearance with and without sortilin and LRP1. This would also enable us to see whether sortilin is capable of clearing Aß when it is not complexed with ApoE and conversely, whether LRP1 is capable of clearing Aß when complexed with ApoE. These experiments may clarify which pathway has the largest influence on Aß clearance. ApoE expression can be controlled by LXRs(17). Therefore, upregulating and downregulating the expression of ApoE with LXR agonists and antagonists in amyloid mouse models to examine the effects on Aß clearance may also be useful. If Aß clearance is increased by ApoE upregulation, then that would support Carlo et al’s finding that ApoE binding to Aß is essential for the latter’s clearance. If Aß clearance is increased by ApoE downregulation, then that would support Verghese et al’s finding that ApoE inhibits Aß clearance. In fact, there have been conflicting results regarding the effects of increasing or decreasing ApoE expression, as upregulating ApoE has been shown to facilitate Aß clearance(18), yet reduced ApoE expression may reduce Aß levels(19). Therefore, modifying ApoE expression in sortilin-expressing, sortilin knock-outs, LRP1- expressing, and LRP1-knock-outs crossed with amyloid mice could also be done to see how these receptors impact Aß clearance depending on the level of ApoE expression.
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NEUR 602: Carlo et al vs Verghese et al Angela Tam
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