Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis
Open accessAbstract
Presenilins (PSs) are components of the γ-secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that γ-secretase is involved in the regulation of cellular lipoprotein uptake. Loss of γ-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 γ-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.
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Altered γ-secretase activity by a PSEN1ΔE9 mutation increases apoE protein levels by interfering with the endocytosis of LDLR.
“Furthermore, altered γ-secretase activity by a PSEN1ΔE9 mutation has been shown to increase apoE protein levels by interfering with the endocytosis of LDLR (Tamboli et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Tamboli et al., 2008
The section “Increased apo E in mouse and human brain with PS1 FAD mutations” reports elevated brain apoE in mice expressing PS1 ΔE9. The section “Inhibition of γ-secretase impairs endocytosis of lipoprotein receptors” reports reduced LDLR endocytosis with PS deficiency or a different, dominant-negative PS1 mutant. The paper does not directly show that ΔE9 impairs LDLR endocytosis or establish that this mechanism causes its apoE increase. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA subsequent study did not support a role of AICD in the transcriptional regulation of LRP1.
“However, a subsequent study did not support a role of AICD in the transcriptional regulation of LRP1 (Tamboli et al., 2008).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Tamboli et al., 2008
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References 76 · Cited by 68
- Authors
- Tamboli, I. Y., Prager, K., Thal, D. R., Thelen, K. M., Dewachter, I., Pietrzik, C. U., St. George-Hyslop, P., Sisodia, S. S., De Strooper, B., Heneka, M. T., Filippov, M. A., Müller, U., van Leuven, F., Lütjohann, D., & Walter, J.
- Affiliations
- University of Bonn (DE)
- Universität Ulm (DE)
- KU Leuven (BE)
- Johannes Gutenberg University Mainz (DE)
- University of Chicago (US)
- Heidelberg University (DE)
- Corresponding author
- Walter, Jochen
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-11-12
- Volume
- 28
- Issue
- 46
- Pages
- 12097-12106
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6671640
- OpenAlex
- W2050989831
- Cited by
- 68
- References
- 76
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 4 · 2013: 3 · 2012: 5
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
- Document Server@UHasselt (UHasselt) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- Wellcome Trust (081864)
- Deutsche Forschungsgemeinschaft (SFB 645)
- Bundesministerium für Bildung und Forschung (01GI0708)
- Rheinische Friedrich-Wilhelms-Universität Bonn
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- gamma-secretase, presenilin 1, lipoprotein uptake, cholesterol biosynthesis, CYP51, apolipoprotein E, early-onset Alzheimer's disease, late-onset Alzheimer's disease
- MeSH terms
- Animals, Apolipoproteins E, Brain, Cholesterol, Endocytosis, Female, Homeostasis, Humans, Lanosterol, Lipoproteins, Male, Membrane Lipids, Neurons, Receptors, LDL, Up-Regulation, Mice, Knockout, Mice, Amyloid Precursor Protein Secretases
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