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Woodruff G, Reyna SM, Dunlap M, Van Der Kant R, Callender JA, Young JE, Roberts EA, Goldstein LS. Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations. Cell Rep. 2016 Oct 11;17(3):759-773. PubMed.
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University of Arkansas for Medical Sciences
This study by Woodruff et al. has provided intriguing new ideas about the roles of enzymes that have previously garnered interest almost exclusively due to their effects on APP. BACE1 and γ-secretase are well-known to have effects on other substrates, and this work ties at least some of those substrates—the lipoprotein receptor family—to these enzymes via the functional interactions between these receptors and APP.
However, there are direct physical interactions between lipoprotein receptors and γ-secretase, too. It has been known for some time that certain lipoprotein receptors are substrates for γ-secretase, and the effects of presenilin mutation or γ-secretase inhibitors on LDL uptake are compelling. Until recently, however, no effect of presenilin mutation on the direct processing of lipoprotein receptors had been documented.
We have now shown (Wang et al., 2016) that three mutations of presenilin-1 impair the processing and/or trafficking of LRP8, a member of the lipoprotein receptor family that is somewhat unusual for the signal transduction pathways it activates in response to Reelin and perhaps other ligands. The effects we uncovered are understandably concentrated on the further processing of the C-terminal "stump" created by sheddases, particularly after Reelin application. Thus, biological consequences may derive primarily from impacts on the gene-regulatory function of the "LICD" (LRP8 C-terminal domain). Nevertheless, we also found changes in the full-length LRP8 in cells expressing mutated presenilin-1. Thus, familial AD mutations in presenilin-1 may dysregulate lipoprotein receptor function, including internalization of lipoprotein particles, due to the status of these receptors as substrates of γ-secretase.
References:
Wang W, Moerman-Herzog AM, Slaton A, Barger SW. Presenilin 1 mutations influence processing and trafficking of the ApoE receptor apoER2. Neurobiol Aging. 2017 Jan;49:145-153. Epub 2016 Oct 11 PubMed.
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