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PMID: 19005074 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 28 ·No. 46 ·2008-11-12 ·Pages 12097-106

Tamboli IY, Prager K, Thal DR, Thelen KM, Dewachter I, Pietrzik CU, St George-Hyslop P, Sisodia SS, De Strooper B, Heneka MT, Filippov MA, Müller U, van Leuven F, Lütjohann D, Walter J

Abstract

Presenilins (PSs) are components of the gamma-secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that gamma-secretase is involved in the regulation of cellular lipoprotein uptake. Loss of gamma-secretase function decreased endocytosis of low-density lipoprotein (LDL) receptor. The decreased uptake of lipoproteins led to upregulation of cellular cholesterol biosynthesis by increased expression of CYP51 and enhanced metabolism of lanosterol. Genetic deletion of PS1 or transgenic expression of PS1 mutants that cause early-onset Alzheimer's disease led to accumulation of gamma-secretase substrates and mistargeting of adaptor proteins that regulate endocytosis of the LDL receptor. Consistent with decreased endocytosis of these receptors, PS1 mutant mice have elevated levels of apolipoprotein E in the brain. Thus, these data demonstrate a functional link between two major genetic factors that cause early-onset and late-onset Alzheimer's disease.

MeSH Terms
Amyloid Precursor Protein Secretases/genetics Animals Apolipoproteins E/metabolism Brain/metabolism Cholesterol/metabolism Endocytosis/physiology Female Homeostasis/physiology Humans Lanosterol/metabolism Lipoproteins/metabolism Male Membrane Lipids/genetics,metabolism Mice Mice, Knockout Neurons/metabolism Receptors, LDL/metabolism Up-Regulation/physiology
Chemicals
Apolipoproteins E Lipoproteins Membrane Lipids Receptors, LDL Lanosterol Cholesterol Amyloid Precursor Protein Secretases
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Tamboli Irfan Y
Department of Neurology, University of Bonn, 53127 Bonn, Germany.
Prager Kai
Thal Dietmar R
Thelen Karin M
Dewachter Ilse
Pietrzik Claus U
St George-Hyslop Peter
Sisodia Sangram S
De Strooper Bart
Heneka Michael T
Filippov Mikhail A
Müller Ulrike
van Leuven Fred
Lütjohann Dieter
Walter Jochen
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.2635-08.2008
Published
2008-11-12
Pages
12097-106
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6671640
Subset
IM
Grants
Wellcome Trust · 081864 · United Kingdom
External Links
PubMed source DOI: 10.1523/JNEUROSCI.2635-08.2008 PMC Full Text View journal details
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