| Schema Description |
apoE, a key protein in lipid transport [1] 29516132
, has three primary Human isoforms, E2, E3, and E4. Compared to the most common isoform (E3), E4 confers substantially higher risk of Alzheimer’s disease: Caucasian individuals homozygous for E4 have an odds ratio of ~14 of being diagnosed with the disease compared with those homozygous for E3 [2] 9343467
. The two isoforms differ by a single SNP, the presence of which in E4 results in a missense substitution C112R. Up to 20 different mechanisms have been proposed to explain the increased risk of E4 compared with E3 [3, 4] 30844401
31367008
.
This is the mechanism schema for one of the proposed mechanisms - a greater abundance of toxic apoE fragments in neurons. In the brain, under normal conditions, apoE is primarily expressed in astrocytes [1] 29516132 , and the protein is not found in neurons [5] 21741992
. apoE has been reported in neurons under some stress conditions [6, 7] 15181247
. There is also evidence that apoE in neurons is potentially subject to proteolysis, producing a range of protein fragments, and that there is a higher fragmentation level for apoE4 than apoE3 [6]. Fragments may be toxic, in two ways. First, by interacting with mitochondria, leading to impaired function/altered glucose metabolism [8] 21118811 , in turn leading impaired neutron function/cell death. Second, interaction with the cyto-skeleton. There are data suggesting a consequence of that interaction is increased p-tau [7] 29632371
, and hence, increased risk of AD. The schema defines the steps in this mechanism and provides links to the commentary and evidence evaluation.
Summary conclusions: For such a long proposed and extensively studied mechanism, the supporting evidence seems surprisingly weak. Critically, it is not clear whether significant amounts of apoE are produced in neurons under any conditions encountered in vivo. In terms of the relationship of this mechanism to established facts about Alzheimer’s, in other mammals, including mice, E4 is the default allele, and so it is surprising that it would have direct toxic consequences. Studies that would most rapidly validate or otherwise this mechanism include better characterization of the iPSC derived cells (how similar to in vivo neurons are these in terms of expression profile for example), measurement of absolute expression levels, comparative studies of the molecular properties of apoE3 and E4 in mouse and human (is there some other change in the human sequence that makes the E4 allele potentially toxic, for example), and better determination of the status of apoE4 expression of human brains, particularly in the presence of Alzheimer’s.
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