In a recent article, Abisambra et al. reported interesting findings related to aberrant low-density lipoprotein receptor (LDLR) levels and subcellular localization in response to the altered APP expression. Using APP transfected human H4 neuroglioma cells, the authors demonstrated that both the mRNA and protein levels of LDLR were increased when compared to the untransfected cells. Accompanied with these expression changes, transport of LDLR to the cell surface was reduced, leading to the aberrant accumulation of LDLR in the trans-Golgi network (TGN). Similar kinds of changes in the expression and localization of LDLR were also observed in Aβ-treated primary neurons and in the hippocampus of APP and PS1 transgenic mice (PSAPP mice). Consistent with these results, LDLR levels were decreased in the brain of APP knockout mice (APP-/-). Finally, the authors provided compelling mechanistic evidence that the altered LDLR transport could be initiated by the disruption of microtubule-organizing center (MTOC) and subsequent destabilization of microtubule network.

The above-mentioned...  Read more

In a recent article, Abisambra et al. reported interesting findings related to aberrant low-density lipoprotein receptor (LDLR) levels and subcellular localization in response to the altered APP expression. Using APP transfected human H4 neuroglioma cells, the authors demonstrated that both the mRNA and protein levels of LDLR were increased when compared to the untransfected cells. Accompanied with these expression changes, transport of LDLR to the cell surface was reduced, leading to the aberrant accumulation of LDLR in the trans-Golgi network (TGN). Similar kinds of changes in the expression and localization of LDLR were also observed in Aβ-treated primary neurons and in the hippocampus of APP and PS1 transgenic mice (PSAPP mice). Consistent with these results, LDLR levels were decreased in the brain of APP knockout mice (APP-/-). Finally, the authors provided compelling mechanistic evidence that the altered LDLR transport could be initiated by the disruption of microtubule-organizing center (MTOC) and subsequent destabilization of microtubule network.

The above-mentioned findings are relevant in the context of the cholesterol transport system, owing to the fact that the LDLR is the key receptor responsible for internalization of ApoE and consequently for the removal of LDL and VLDL from the blood. Related to this, LDLR gene variants have been shown to associate with increased risk of Alzheimer disease (AD) in APOE ε4 allele carriers (see details), which again emphasizes the possible role of LDLR in AD pathogenesis. According to the above-mentioned findings, reduced levels of LDLR in the cell surface under APP and Aβ overexpression may lead to impaired cholesterol transport, which in turn may reduce intracellular cholesterol levels. Low levels of intracellular sterols may again induce the transcription of the LDLR gene as a compensatory mechanism, thus explaining the observed increase in the expression of LDLR. Since the authors suggested that the initiating event in the aberrant trafficking of LDLR is the global disruption of the microtubule trafficking system, it is anticipated that several other targets, in addition to LDLR, will be discovered that are also affected by the altered expression of APP. On this point, however, it should be noted that the LDLR-related protein (LRP), which is a receptor that also internalizes ApoE, did not show any changes in subcellular localization after APP overexpression in H4 cells.

Since it was recently also shown that APP regulates L-type calcium channel levels in the plasma membrane (Yang et al., 2009) similarly to LDLR, it is tempting to speculate that APP encompasses a much broader role in the protein trafficking beyond current knowledge. This suggests that changes in the APP expression and/or processing typically observed in AD could then interfere with the trafficking of a large set of different proteins. Identification and functional characterization of these targets may eventually open new avenues to assess the underlying disease process and possibly enable researchers to find novel drug targets.

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