Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10

Kojro, Elzbieta; Gimpl, Gerald; Lammich, Sven; März, Winfried; Fahrenholz, Falk

doi:10.1073/pnas.081612998

Cited by 804Alzheimer's disease research and treatmentsCholesterol and Lipid MetabolismDementia and Cognitive Impairment Research

Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10

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Kojro, Elzbieta, Gimpl, Gerald, Lammich, Sven, März, Winfried, Fahrenholz, Falk·2001·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.081612998PMC PMC33296

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Abstract

Biochemical, epidemiological, and genetic findings demonstrate a link between cholesterol levels, processing of the amyloid precursor protein (APP), and Alzheimer's disease. In the present report, we identify the α-secretase ADAM 10 ( a d isintegrin a nd m etalloprotease) as a major target of the cholesterol effects on APP metabolism. Treatment of various peripheral and neural cell lines with either the cholesterol-extracting agent methyl-β-cyclodextrin or the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin resulted in a drastic increase of secreted α-secretase cleaved soluble APP. This strong stimulatory effect was in the range obtained with phorbol esters and was further increased in cells overexpressing ADAM 10. In cells overexpressing APP, the increase of α-secretase activity resulted in a decreased secretion of Aβ peptides. Several mechanisms were elucidated as being the basis of enhanced α-secretase activity: increased membrane fluidity and impaired internalization of APP were responsible for the effect observed with methyl-β-cyclodextrin; treatment with lovastatin resulted in higher expression of the α-secretase ADAM 10. Our results demonstrate that cholesterol reduction promotes the nonamyloidogenic α-secretase pathway and the formation of neuroprotective α-secretase cleaved soluble APP by several mechanisms and suggest approaches to prevention of or therapy for Alzheimer's disease.

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APOE isoforms likely influence Aβ production by modulating lipid metabolism and the lipid composition of cellular membranes, with APOE4 promoting amyloidogenic APP cleavage and Aβ production more than APOE3.
“APOE isoforms likely influence Aβ production by modulating lipid metabolism and the lipid composition of cellular membranes, with APOE4 promoting amyloidogenic APP cleavage and Aβ production more than APOE3 [8–10].”
From Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE (2024) · cites this paper as [8]
The Discussion reports that ApoE4 is a weaker lipid acceptor than ApoE3 and suggests that its lower cholesterol efflux reduces nonamyloidogenic α-secretase activity. It also reports that cholesterol depletion reduces Aβ secretion, but does not directly show that ApoE4 causes more amyloidogenic APP cleavage or Aβ production than ApoE3. (LLM, conf=0.84)
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APOE modulates APP metabolism in an isoform-dependent manner through distinct mechanisms, including influencing APP processing via effects on lipid metabolism and modulating Aβ clearance and aggregation via the formation of APOE-Aβ complexes.
“APOE modulates APP metabolism in an isoform-dependent manner through distinct mechanisms: 1) influencing APP processing via effects on lipid metabolism [8–10], and 2) modulating Aβ clearance and aggregation via the formation of APOE-Aβ complexes [11, 12].”
From Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE (2024) · cites this paper as [8]
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A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751 · see citing works
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/y59-099 · Cited by 23,189 · see citing works
Functional rafts in cell membranes
Simons, K., & Ikonen, E. (1997) · Nature · doi:10.1038/42408 · Cited by 9,757 · see citing works
Regulation of Renal Organic Anion Transporter 3 (SLC22A8) Expression and Function by the Integrity of Lipid Raft Domains and their Associated Cytoskeleton
Srimaroeng, C., Cecile, J. P., Walden, R., & Pritchard, J. B. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350077 · Cited by 2,989 · see citing works
Caveolin, a protein component of caveolae membrane coats
Rothberg, K. G., Heuser, J. E., Donzell, W. C., Ying, Y., Glenney, J. R., & Anderson, R. G. W. (1992) · Cell · doi:10.1016/0092-8674(92)90143-z · Cited by 2,259 · see citing works
Statins and the risk of dementia
Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S. S., & Drachman, D. (2000) · The Lancet · doi:10.1016/s0140-6736(00)03155-x · Cited by 1,763 · see citing works
Cleavage of Amyloid β Peptide During Constitutive Processing of Its Precursor
Esch, F. S., Keim, P. S., Beattie, E. C., Blacher, R. W., Culwell, A. R., Oltersdorf, T., McClure, D., & Ward, P. J. (1990) · Science · doi:10.1126/science.2111583 · Cited by 1,403 · see citing works
Lipid Domain Structure of the Plasma Membrane Revealed by Patching of Membrane Components
Harder, T., Scheiffele, P., Verkade, P., & Simons, K. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.141.4.929 · Cited by 1,186 · see citing works
Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons
Simons, M., Keller, P., Strooper, B. D., Beyreuther, K. T., Dotti, C. G., & Simons, K. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6460 · Cited by 1,167 · see citing works
Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease
Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, R., Jasionowski, M., Haass, C., & Fahrenholz, F. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.3922 · Cited by 1,132 · see citing works
Self-citation
Extraction of Cholesterol with Methyl-β-Cyclodextrin Perturbs Formation of Clathrin-coated Endocytic Vesicles
Rodal, S. K., Skretting, G., Garred, Ø., Vilhardt, F., van Deurs, B., & Sandvig, K. (1999) · Molecular Biology of the Cell · doi:10.1091/mbc.10.4.961 · Cited by 1,009 · see citing works
Hypercholesterolemia Accelerates the Alzheimer's Amyloid Pathology in a Transgenic Mouse Model
Refolo, L. M., Pappolla, M. A., Malester, B., LaFrancois, J. J., Bryant‐Thomas, T., Wang, R., Tint, G. S., Sambamurti, K., & Duff, K. (2000) · Neurobiology of Disease · doi:10.1006/nbdi.2000.0304 · Cited by 1,003 · see citing works
Evidence That Tumor Necrosis Factor α Converting Enzyme Is Involved in Regulated α-Secretase Cleavage of the Alzheimer Amyloid Protein Precursor
Buxbaum, J. D., Liu, K.-N., Luo, Y., Slack, J. L., Stocking, K. L., Peschon, J. J., Johnson, R. S., Castner, B. J., Cerretti, D. P., & Black, R. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.43.27765 · Cited by 933 · see citing works
Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments
Haass, C., Koo, E., Mellon, A., Hung, A. Y., & Selkoe, D. (1992) · Nature · doi:10.1038/357500a0 · Cited by 901 · see citing works
Untitled work
(1985) · PubMed · Cited by 706 · see citing works
Proteolytic processing and cell biological functions of the amyloid precursor protein
Strooper, B. D., & Annaert, W. G. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.11.1857 · Cited by 628 · see citing works
Acute cholesterol depletion inhibits clathrin-coated pit budding
Subtil, A., Gaidarov, I., Kobylarz, K. A., Lampson, M. A., Keen, J. H., & McGraw, T. E. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.12.6775 · Cited by 577 · see citing works
Alteration of the Myometrial Plasma Membrane Cholesterol Content with .beta.-Cyclodextrin Modulates the Binding Affinity of the Oxytocin Receptor
Klein, U., Gimpl, G., & Fahrenholz, F. (1995) · Biochemistry · doi:10.1021/bi00042a009 · Cited by 547 · see citing works
Self-citation
Cholesterol as Modulator of Receptor Function
Gimpl, G., Bürger, K., & Fahrenholz, F. (1997) · Biochemistry · doi:10.1021/bi963138w · Cited by 454 · see citing works
Self-citation
Cholesterol Modulates α-Secretase Cleavage of Amyloid Precursor Protein
Bodovitz, S., & Klein, W. L. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.8.4436 · Cited by 447 · see citing works
Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact.
Shivers, B. D., Hilbich, C., Multhaup, G., Salbaum, M., Beyreuther, K. T., & SEEBURG, P. H. (1988) · The EMBO Journal · doi:10.1002/j.1460-2075.1988.tb02952.x · Cited by 442 · see citing works
Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation.
Smart, E. J., Ying, Y. S., Conrad, P. A., et al. (1994) · The Journal of Cell Biology · doi:10.1083/jcb.127.5.1185 · Cited by 424 · see citing works
Maturation and Endosomal Targeting of β-Site Amyloid Precursor Protein-cleaving Enzyme
Huse, J. T., Pijak, D. S., Leslie, G. J., Lee, V. M.-Y., & Doms, R. W. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004175200 · Cited by 402 · see citing works
A detergent-insoluble membrance compartment contains Aβ in vivo
Lee, S., Liyanage, U. K., Bickel, P. E., Xia, W., Lansbury, P. T., & Kosik, K. S. (1998) · Nature Medicine · doi:10.1038/nm0698-730 · Cited by 395 · see citing works
A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth
Small, D. H., Nurcombe, V., Reed, G., Clarris, H. J., Moir, R. D., Beyreuther, K. T., & Masters, C. L. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-04-02117.1994 · Cited by 389 · see citing works
Mutagenesis Identifies New Signals for β-Amyloid Precursor Protein Endocytosis, Turnover, and the Generation of Secreted Fragments, Including Aβ42
Perez, R. G., Soriano, S., Hayes, J. D., Ostaszewski, B. L., Xia, W., Selkoe, D. J., Chen, X., Stokin, G. B., & Koo, E. H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.27.18851 · Cited by 387 · see citing works
Memory-enhancing effects of secreted forms of the β-amyloid precursor protein in normal and amnestic mice
Méziane, H., Dodart, J., Mathis, C., Little, S. H., Clemens, J. A., Paul, S. M., & Ungerer, A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.21.12683 · Cited by 355 · see citing works
Activation of K+ channels and suppression of neuronal activity by secreted β-amyloid-precursor protein
Furukawa, K., Barger, S. W., Blalock, E. M., & Mattson, M. P. (1996) · Nature · doi:10.1038/379074a0 · Cited by 332 · see citing works
Human apolipoprotein E: the Alzheimer's disease connection
Weisgraber, K. H., & Mahley, R. W. (1996) · The FASEB Journal · doi:10.1096/fasebj.10.13.8940294 · Cited by 327 · see citing works
Membrane-anchored metalloprotease MDC9 has an α-secretase activity responsible for processing the amyloid precursor protein
KOIKE, H., Tomioka, S., Sorimachi, H., Saido, T. C., Maruyama, K., Okuyama, A., Fujisawa‐Sehara, A., Ohno, S., Suzuki, K., & Ishiura, S. (1999) · Biochemical Journal · doi:10.1042/bj3430371 · Cited by 278 · see citing works
The beta-amyloid protein precursor of Alzheimer disease has soluble derivatives found in human brain and cerebrospinal fluid.
Palmert, M. R., Podlisny, M. B., Witker, D. S., Oltersdorf, T., Younkin, L. H., Selkoe, D. J., & Younkin, S. G. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.16.6338 · Cited by 254 · see citing works
Apolipoprotein E exhibits isoform‐specific promotion of lipid efflux from astrocytes and neurons in culture
Michikawa, M., Fan, Q., Isobe, I., & Yanagisawa, K. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0741008.x · Cited by 244 · see citing works
Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein.
Parker, M. W., Rossjohn, J., Cappai, R., Feil, S. C., Henry, A., McKinstry, W. J., Galatis, D., Hesse, L., Multhaup, G., Beyreuther, K. T., et al. (1999) · Nature Structural Biology · doi:10.1038/7562 · Cited by 242 · see citing works
Trophic effect of β-amyloid precursor protein on cerebral cortical neurons in culture
Araki, W., Kitaguchi, N., Tokushima, Y., Ishii, K., Aratake, H., Shimohama, S., Nakamura, S., & Kimura, J. (1991) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(05)81412-3 · Cited by 213 · see citing works
Identification of the Alzheimer beta/A4 amyloid precursor protein in clathrin-coated vesicles purified from PC12 cells.
Nordstedt, C., Caporaso, G. L., Thyberg, J., Gandy, S., & Greengard, P. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)54194-6 · Cited by 208 · see citing works
In Vivo and in Vitro Blood–Brain Barrier Transport of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors
Saheki, A., Terasaki, T., Tamai, I., & Tsuji, A. (1994) · Pharmaceutical Research · doi:10.1023/a:1018975928974 · Cited by 206 · see citing works
Cleavage of Alzheimer's Amyloid Precursor Protein by α-Secretase Occurs at the Surface of Neuronal Cells
Parvathy, S., Hussain, I., Karran, E. H., Turner, A. J., & Hooper, N. M. (1999) · Biochemistry · doi:10.1021/bi9906827 · Cited by 200 · see citing works
Secreted β-Amyloid Precursor Protein Counteracts the Proapoptotic Action of Mutant Presenilin-1 by Activation of NF-κB and Stabilization of Calcium Homeostasis
Guo, Q., Robinson, N., & Mattson, M. P. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.20.12341 · Cited by 196 · see citing works
Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation
Steiner, H., Capell, A., Pesold, B., Citron, M., Kloetzel, P. M., Selkoe, D. J., Romig, H., Mendla, K. D., & Haass, C. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.48.32322 · Cited by 194 · see citing works
Coordinated Expression of β‐Amyloid Precursor Protein and the Putative β‐Secretase BACE and α‐Secretase ADAM10 in Mouse and Human Brain
Marcinkiewicz, M. M., & Seidah, N. G. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0752133.x · Cited by 185 · see citing works
Caveolae, Plasma Membrane Microdomains for α-Secretase-mediated Processing of the Amyloid Precursor Protein
Ikezu, T., Trapp, B. D., Song, K. S., Schlegel, A., Lisanti, M. P., & Okamoto, T. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.17.10485 · Cited by 157 · see citing works
Secretory processing of amyloid precursor protein is inhibited by increase in cellular cholesterol content
Racchi, M., Baetta, R., Salvietti, N., Ianna, P., Franceschini, G., Paoletti, R., Fumagalli, R., Govoni, S. M., Trabucchi, M., & Soma, M. R. (1997) · Biochemical Journal · doi:10.1042/bj3220893 · Cited by 151 · see citing works
Axonal Amyloid Precursor Protein Expressed by Neurons in Vitro Is Present in a Membrane Fraction with Caveolae-like Properties
Bouillot, C., Prochiantz, A., Rougon, G. N., & Allinquant, B. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.13.7640 · Cited by 137 · see citing works
Trafficking of cell-surface amyloid β-protein precursor: II. Endocytosis, recycling, and lysosomal targeting detected by immunolocalization
Yamazaki, T., Koo, E. H., & Selkoe, D. J. (1996) · Journal of Cell Science · doi:10.1242/jcs.109.5.999 · Cited by 135 · see citing works
Cholesterol decreases secretion of the secreted form of amyloid precursor protein by interfering with glycosylation in the protein secretory pathway
Galbete, J. L., Martin, T. R., PERESSINI, E., Modena, P., Bianchi, R., & Forloni, G. (2000) · Biochemical Journal · doi:10.1042/bj3480307 · Cited by 97 · see citing works
Involvement of amyloid precursor protein in functional synapse formation in cultured hippocampal neurons
Morimoto, T., Ohsawa, I., Takamura, C., Ishiguro, M., & Kohsaka, S. (1998) · Journal of Neuroscience Research · doi:10.1002/(sici)1097-4547(19980115)51:2 · Cited by 85 · see citing works
Genetic Defects in Postsqualene Cholesterol Biosynthesis
Moebius, F. F., Fitzky, B. U., & Glossmann, H. H. (2000) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(00)00235-6 · Cited by 60 · see citing works
The Amyloid Precursor Protein Is Not Enriched in Caveolae‐Like, Detergent‐Insoluble Membrane Microdomains
Parkin, E. T., Hussain, I., Turner, A. J., et al. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69052179.x · Cited by 35 · see citing works
Genetic epidemiology of Alzheimerʼs disease
Dartigues, J. F., & Letenneur, L. (2000) · Current Opinion in Neurology · doi:10.1097/00019052-200008000-00004 · Cited by 20 · see citing works
Defective utilization of cholesterol esters from low-density lipoprotein in a human acute lymphoblastic leukemia T cell line
Cutts, J., & Melnykovych, G. (1988) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(88)90131-2 · Cited by 12 · see citing works

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[29]Subtil, A., Gaidarow, I., Kobylarz, K., Lampson, M. A., Keen, J. H. & McGraw, T. E. (1999) Proc. Natl. Acad. Sci. USA 96, 6775-6780.

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Barage, S. H., & Sonawane, K. D. (2015) · Neuropeptides · doi:10.1016/j.npep.2015.06.008 · Cited by 579 · see citing works
Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins
Casserly, I., & Topol, E. J. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15900-x · Cited by 560 · see citing works
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Eckert, G. P., Chang, S., Eckmann, J., Copanaki, E., Hagl, S., Hener, U., Müller, W. E., & Kögel, D. (2011) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2010.10.014 · Cited by 92 · see citing works
Role of amyloid beta in lipid homeostasis
Grösgen, S., Grimm, M. O. W., Frieß, P., & Hartmann, T. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.05.002 · Cited by 90 · see citing works
ApoER2 expression increases Aβ production while decreasing Amyloid Precursor Protein (APP) endocytosis: possible role in the partitioning of APP into lipid rafts and in the regulation of γ-secretase activity
Fuentealba, R. A., Barría, M. I., Lee, J., Cam, J., Araya, C., Escudero, C. A., Inestrosa, N. C., Bronfman, F. C., Bu, G., & Marzolo, M.-P. (2007) · Molecular Neurodegeneration · doi:10.1186/1750-1326-2-14 · Cited by 70 · see citing works
Effects of plasmalogens on systemic lipopolysaccharide‐induced glial activation and β‐amyloid accumulation in adult mice
Katafuchi, T., Ifuku, M., Mawatari, S., Noda, M., Miake, K., Sugiyama, M., & Fujino, T. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06641.x · Cited by 68 · see citing works
Anti-inflammatory and Immune Therapy for Alzheimers Disease: Current Status and Future Directions
Walker, D., & Lue, L.-F. (2007) · Current Neuropharmacology · doi:10.2174/157015907782793667 · Cited by 66 · see citing works
Cholesterol homeostasis failure in the brain: Implications for synaptic dysfunction and cognitive decline
Segatto, M., Leboffe, L., Trapani, L., & Pallottini, V. (2014) · Current Medicinal Chemistry · doi:10.2174/0929867321666140303142902 · Cited by 65 · see citing works
Cholesterol metabolism, apolipoprotein E, adenosine triphosphate-binding cassette transporters, and Alzheimer's disease
Hirsch-Reinshagen, V., & Wellington, C. L. (2007) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32813aeabf · Cited by 61 · see citing works
A New Hypothesis for Alzheimer’s Disease: The Lipid Invasion Model
Rudge, J. D. (2022) · Journal of Alzheimer's Disease Reports · doi:10.3233/adr-210299 · Cited by 58 · see citing works
Increased expression of cholesterol transporter ABCA1 is highly correlated with severity of dementia in AD hippocampus
Akram, A., Schmeidler, J., Katsel, P., Hof, P. R., & Haroutunian, V. (2010) · Brain Research · doi:10.1016/j.brainres.2010.01.006 · Cited by 50 · see citing works
Cognitive Performance and Plasma Levels of Homocysteine, Vitamin B12, Folate and Lipids in Patients with Alzheimer Disease
Li, L., Cao, D., Desmond, R., Rahman, A., Lah, J. J., Levey, A. I., & Zamrini, E. (2008) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000164271 · Cited by 45 · see citing works
Anti-amyloidogenic effect of Allium sativum in Alzheimer’s transgenic model Tg2576
Chauhan, N. B. (2003) · Journal of Herbal Pharmacotherapy · doi:10.1080/j157v03n01_05 · Cited by 39 · see citing works
Biological consequences of statins in Candida species and possible implications for human health
Wikhe, K., Westermeyer, C., & Macreadie, I. G. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351529 · Cited by 31 · see citing works
Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE
Yesiltepe, M., Yin, T., Tambini, M., Bao, H., Pan, M., d’Abramo, C., Giliberto, L., Han, X., & D’Adamio, L. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01832-2 · Cited by 10 · see citing works
“APOE isoforms likely influence Aβ production by modulating lipid metabolism and the lipid composition of cellular membranes, with APOE4 promoting amyloidogenic APP cleavage and Aβ production more than APOE3 [8–10].”
Background

The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by α-secretase ADAM10
Hitschler, L., & Lang, T. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101911 · Cited by 11 · see citing works
Putative function of ADAM9, ADAM10, and ADAM17 as APP -secretase
Asai, M., Hattori, C., Szabó, B., Sasagawa, N., Maruyama, K., Tanuma, S.-I., & Ishiura, S. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02999-6 · Cited by 303 · see citing works
P4–267: ADAM10 activation is required for green tea EGCG–induced alpha–secretase cleavage of amyloid precursor protein
Tan, J., Obregon, D. F., Rezai-Zadeh, K. P., et al. (2006) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2006.05.2006 · Cited by 4 · see citing works
ADAM10 is the physiologically relevant, constitutive α‐secretase of the amyloid precursor protein in primary neurons
Kuhn, P., Wang, H., Dislich, B., Colombo, A., Zeitschel, U., Ellwart, J. W., Kremmer, E., Roßner, S., & Lichtenthaler, S. F. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.167 · Cited by 621 · see citing works
α-secretase ADAM10 physically interacts with β-secretase BACE1 in neurons and regulates CHL1 proteolysis
Wang, X., Wang, C., & Pei, G. (2018) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjy001 · Cited by 17 · see citing works

Authors: Kojro, E., Gimpl, G., Lammich, S., März, W., & Fahrenholz, F.
Affiliations: Institute of Biochemistry, Johannes Gutenberg University, Becherweg 30, D-55128 Mainz, Germany; and Department of Clinical Chemistry, Albert Ludwigs University, Hugstetterstrasse 55, D-79106 Freiburg, Germany
University of Freiburg (DE)
ORCID: Gimpl, Gerald
März, Winfried
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2001-04-17
Volume: 98
Issue: 10
Pages: 5815-5820
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.081612998
PMC: PMC33296
OpenAlex: W2009111659
Cited by: 804
References: 51
Citations by year: 2026: 6 · 2025: 10 · 2024: 17 · 2023: 13 · 2022: 22 · 2021: 18 · 2020: 23 · 2019: 17 · 2018: 21 · 2017: 23 · 2016: 23 · 2015: 20 · 2014: 32 · 2013: 28 · 2012: 36
FWCI: 32.48
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: cholesterol, ADAM10, alpha-secretase, amyloid precursor protein, non-amyloidogenic pathway, Alzheimer's disease, amyloid-beta, methyl-β-cyclodextrin, lovastatin, membrane fluidity, phorbol ester
MeSH terms: ADAM10 Protein, Anticholesteremic Agents, Cell Compartmentation, Cell Membrane, Cholesterol, Endocytosis, Humans, Lovastatin, Membrane Fluidity, Membrane Proteins, Metalloendopeptidases, Amyloid beta-Protein Precursor, Hydroxymethylglutaryl-CoA Reductase Inhibitors, ADAM Proteins, Amyloid Precursor Protein Secretases

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Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10

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