Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis.
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.
Tamboli
Irfan Y
IY
Department of Neurology, University of Bonn, 53127 Bonn, Germany.
Prager
Kai
K
Thal
Dietmar R
DR
Thelen
Karin M
KM
Dewachter
Ilse
I
Pietrzik
Claus U
CU
St George-Hyslop
Peter
P
Sisodia
Sangram S
SS
De Strooper
Bart
B
Heneka
Michael T
MT
Filippov
Mikhail A
MA
Müller
Ulrike
U
van Leuven
Fred
F
Lütjohann
Dieter
D
Walter
Jochen
J
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007810:Lanosterol / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008297:Male; D008563:Membrane Lipids / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D001057:Apolipoproteins E; D008074:Lipoproteins; D008563:Membrane Lipids; D011973:Receptors, LDL; D007810:Lanosterol; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases