PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates hepatic low-density lipoprotein receptor (LDLR) levels in humans. PCSK9 has also been shown to regulate the levels of additional membrane-bound proteins in vitro, including the very low-density lipoprotein receptor (VLDLR), apolipoprotein E receptor 2 (ApoER2) and the beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), which are all highly expressed in the CNS and have been implicated in Alzheimer's disease. To better understand the role of PCSK9 in regulating these additional target proteins in vivo, their steady-state levels were measured in the brain of wild-type, PCSK9-deficient, and human PCSK9 overexpressing transgenic mice. We found that while PCSK9 directly bound to recombinant LDLR, VLDLR, and apoER2 protein in vitro, changes in PCSK9 expression did not alter the level of these receptors in the mouse brain. In addition, we found no evidence that PCSK9 regulates BACE1 levels or APP processing in the mouse brain. In conclusion, our results suggest that while PCSK9 plays an important role in regulating circulating LDL cholesterol levels by reducing the number of hepatic LDLRs, it does not appear to modulate the levels of LDLR and other membrane-bound proteins in the adult mouse brain.
Liu
Mali
M
Neurology Department, Merck Research Laboratories, West Point, PA, USA.
Wu
Guoxin
G
Baysarowich
Jennifer
J
Kavana
Michael
M
Addona
George H
GH
Bierilo
Kathleen K
KK
Mudgett
John S
JS
Pavlovic
Guillaume
G
Sitlani
Ayesha
A
Renger
John J
JJ
Hubbard
Brian K
BK
Fisher
Timothy S
TS
Zerbinatti
Celina V
CV
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011485:Protein Binding; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D011973:Receptors, LDL; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; D053829:Amyloid Precursor Protein Secretases; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
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