Huang YA, Zhou B, Wernig M, Südhof TC.
ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion.
Cell. 2017 Jan 26;168(3):427-441.e21. Epub 2017 Jan 19
PubMed.
The work of Huang et al. is very interesting in its finding that one of the mechanisms of ApoE altering Alzheimer’s disease risk is through neuronal signal transduction, involving DLK, ERK, and cFos. The data show that the three ApoE isoforms differentially affect APP transcription and Aβ production, with effects that parallel ApoE-related risk (ApoE2<ApoE3<ApoE4). An interesting aspect of this model is that ApoE is affecting brain function before the appearance of pathological changes, and thus dependent on the authors using models of normal tissue. Interestingly, the glial factors initially identified that induced APP and Aβ were related to changes in lipid metabolism (ApoE lipoproteins) and glucose metabolism (insulin growth factor 2 and its binding protein); these factors may help explain the strong acute induction of APP after many models of brain injury.
Technically, this work shows the great promise of CRISPRi technology in defining numerous members of complex pathways. In complex conditions like AD, which involve effects over many years of aging, single pathways will not be enough to explain subtle changes to pathogenesis over time. Future work in this area will surely examine whether there is evidence of the ApoE effects on this signal transduction pathway in control brains in mice and humans, adding data on chronic effects to the current data on acute effects.
Previous studies have supported differential effects of ApoE isoforms on Aβ clearance, aggregation and toxicity. This study, using human neurons, suggests that ApoE isoform effects relevant to AD might also include impact on Aβ production through modulating APP expression. Specific contribution of individual pathways to AD risk require further studies using in vivo models and in humans.
The cellular and biochemical experiments elegantly showed that ApoE isoforms have different effects (ApoE4>ApoE3>ApoE2) on stimulating a signaling pathway in neurons that includes the DLK/MKK7/ERK1/2 MAP kinase pathway and cFos phosphorylation, impacting APP gene transcription. It will be interesting to examine whether such signaling has physiological functions by perhaps influencing neuronal and synaptic functions.
Validation using in vivo model systems expressing different human APOE gene alleles will be important. For example, the effects of ApoE gene alleles on APP expression could be evaluated using human APOE targeted replacement (TR) mice. Changes in expression of the endogenous mouse APP gene or the human APP gene (e.g., YAC-APP Tg mice) as a result of ApoE isoform expression (targeted replacement or AAV viral mediated) could be evaluated.
A critical relevance of this work is that it was performed using ES- and iPS cell-derived human neurons. However, the relevance to human brain, in particular aging brains that are more relevant to AD, requires further investigation.
The authors indicated that ApoE particles secreted by HEK293 cells are lipidated, containing cholesterol, however, there is little support for such a conclusion from the literature or this study. In fact, published work suggests that ApoE particles secreted by HEK cells are not lipidated, rather they are mostly just ApoE aggregates (LaDu et al., 2006). ApoE/lipoprotein particles secreted by astrocytes (primary cells from ApoE-TR mice or iPSC-derived) are truly lipidated particles and should be tested in these assays.
The results using the lipoprotein receptor antagonist RAP are interesting, as they suggest an involvement of RAP-responsive ApoE receptors, which could either be ApoE signaling receptors (e.g., ApoER2 and VLDLR) or metabolic receptors (e.g., LRP1 and LDLR). Further studies are needed to sort out the receptor(s) involved. That could help elucidate the physiological and pathological pathways relevant to ApoE and/or the receptor.
References:
LaDu MJ, Stine WB Jr, Narita M, Getz GS, Reardon CA, Bu G.
Self-assembly of HEK cell-secreted ApoE particles resembles ApoE enrichment of lipoproteins as a ligand for the LDL receptor-related protein.
Biochemistry. 2006 Jan 17;45(2):381-90.
PubMed.
Comments
Georgetown University
The work of Huang et al. is very interesting in its finding that one of the mechanisms of ApoE altering Alzheimer’s disease risk is through neuronal signal transduction, involving DLK, ERK, and cFos. The data show that the three ApoE isoforms differentially affect APP transcription and Aβ production, with effects that parallel ApoE-related risk (ApoE2<ApoE3<ApoE4). An interesting aspect of this model is that ApoE is affecting brain function before the appearance of pathological changes, and thus dependent on the authors using models of normal tissue. Interestingly, the glial factors initially identified that induced APP and Aβ were related to changes in lipid metabolism (ApoE lipoproteins) and glucose metabolism (insulin growth factor 2 and its binding protein); these factors may help explain the strong acute induction of APP after many models of brain injury.
Technically, this work shows the great promise of CRISPRi technology in defining numerous members of complex pathways. In complex conditions like AD, which involve effects over many years of aging, single pathways will not be enough to explain subtle changes to pathogenesis over time. Future work in this area will surely examine whether there is evidence of the ApoE effects on this signal transduction pathway in control brains in mice and humans, adding data on chronic effects to the current data on acute effects.
View all comments by G. William RebeckHong Kong University of Science & Technology
Previous studies have supported differential effects of ApoE isoforms on Aβ clearance, aggregation and toxicity. This study, using human neurons, suggests that ApoE isoform effects relevant to AD might also include impact on Aβ production through modulating APP expression. Specific contribution of individual pathways to AD risk require further studies using in vivo models and in humans.
The cellular and biochemical experiments elegantly showed that ApoE isoforms have different effects (ApoE4>ApoE3>ApoE2) on stimulating a signaling pathway in neurons that includes the DLK/MKK7/ERK1/2 MAP kinase pathway and cFos phosphorylation, impacting APP gene transcription. It will be interesting to examine whether such signaling has physiological functions by perhaps influencing neuronal and synaptic functions.
Validation using in vivo model systems expressing different human APOE gene alleles will be important. For example, the effects of ApoE gene alleles on APP expression could be evaluated using human APOE targeted replacement (TR) mice. Changes in expression of the endogenous mouse APP gene or the human APP gene (e.g., YAC-APP Tg mice) as a result of ApoE isoform expression (targeted replacement or AAV viral mediated) could be evaluated.
A critical relevance of this work is that it was performed using ES- and iPS cell-derived human neurons. However, the relevance to human brain, in particular aging brains that are more relevant to AD, requires further investigation.
The authors indicated that ApoE particles secreted by HEK293 cells are lipidated, containing cholesterol, however, there is little support for such a conclusion from the literature or this study. In fact, published work suggests that ApoE particles secreted by HEK cells are not lipidated, rather they are mostly just ApoE aggregates (LaDu et al., 2006). ApoE/lipoprotein particles secreted by astrocytes (primary cells from ApoE-TR mice or iPSC-derived) are truly lipidated particles and should be tested in these assays.
The results using the lipoprotein receptor antagonist RAP are interesting, as they suggest an involvement of RAP-responsive ApoE receptors, which could either be ApoE signaling receptors (e.g., ApoER2 and VLDLR) or metabolic receptors (e.g., LRP1 and LDLR). Further studies are needed to sort out the receptor(s) involved. That could help elucidate the physiological and pathological pathways relevant to ApoE and/or the receptor.
References:
LaDu MJ, Stine WB Jr, Narita M, Getz GS, Reardon CA, Bu G. Self-assembly of HEK cell-secreted ApoE particles resembles ApoE enrichment of lipoproteins as a ligand for the LDL receptor-related protein. Biochemistry. 2006 Jan 17;45(2):381-90. PubMed.
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