β‐Site APP cleaving enzyme up‐regulation induced by 4‐hydroxynonenal is mediated by stress‐activated protein kinases pathways
Abstract
4‐Hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, up‐regulates expression of the β‐site APP cleaving enzyme (BACE‐1), an aspartyl protease responsible for the β‐secretase cleavage of amyloid precursor protein (AβPP), and results in increased levels of amyloid β (Aβ) peptide. The mechanisms underlying this remain unclear but are of fundamental importance because prevention of BACE‐1 up‐regulation is viewed as an important therapeutic strategy. In this study, we exposed NT 2 neurons to a range of HNE concentrations (0.5–5 µ m ) that elicited an up‐regulation of BACE‐1 expression, a significant increase in intracellular and secreted levels of Aβ peptides as well as apoptosis involving poly‐ADP ribose polymerase cleavage and activation of caspase 3. To delineate the molecular events involved in HNE‐mediated BACE‐1 activation, we investigated the involvement of stress‐activated protein kinases (SAPK), signal transducers and activators of transcription (STAT) and serine–threonine kinase B/phosphatidylinositol phosphate 3 kinase (Akt/PtdIns3K). Using specific pharmacological inhibitors, our results show that activation of c‐Jun N‐terminal kinases and p38 MAPK. , but not STAT or Akt/PtdIns3K, pathways mediate the HNE‐dependent up‐regulation of BACE‐1 expression. Therefore, HNE, an oxidative stress mediator detected in vivo in the brains of Alzheimer's disease patients, may play a pathogenetic role in Alzheimer's disease by selectively activating SAPK pathways and BACE‐1 that regulate the proteolytic processing of AβPP.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Oxidative stress increases Aβ generation.
“consequently, increased Aβ generation”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Tamagno et al., 2005
Oxidative stress-induced β-secretase upregulation and increased Aβ generation are preventable by antioxidant treatment in vitro.
“both of which are preventable by antioxidant treatment in vitro”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Tamagno et al., 2005
Oxidative stress induces β-secretase upregulation.
“Oxidative stress also induces β-secretase upregulation”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Tamagno et al., 2005
Cites
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876 · see citing works
Misonou, H., Morishima-Kawashima, M., & Ihara, Y. (2000) · Biochemistry · doi:10.1021/bi000169p · Cited by 304 · see citing works
Savage, M. J., Lin, Y.-G., Ciallella, J. R., Flood, D. G., & Scott, R. W. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-09-03376.2002 · Cited by 291 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455 · see citing works
Pathological roles of MAPK signaling pathways in human diseases
Kim, E. K., & Choi, E.-J. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.12.009 · Cited by 2,472 · see citing works
Mitochondria take center stage in aging and neurodegeneration
Beal, M. F. (2005) · Annals of Neurology · doi:10.1002/ana.20624 · Cited by 957 · see citing works
Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease?
Johnson, V. E., Stewart, W., & Smith, D. H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2808 · Cited by 587 · see citing works
The Alzheimer's disease Beta-secretase enzyme, BACE1
Cole, S. L., & Vassar, R. (2007) · Molecular Neurodegeneration · doi:10.1186/1750-1326-2-22 · Cited by 550 · see citing works
Neuroprotective effects of curcumin
Cole, G. M., Teter, B., & Frautschy, S. A. (2007) · ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY · doi:10.1007/978-0-387-46401-5_8 · Cited by 516 · see citing works
McManus, M. J., Murphy, M. P., & Franklin, J. L. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0552-11.2011 · Cited by 432 · see citing works
He, P., Zhong, Z., Lindholm, K., Berning, L., Lee, W., Lemere, C., Staufenbiel, M., Li, R., & Shen, Y. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200705042 · Cited by 390 · see citing works
Neuroprotective strategies involving ROS in Alzheimer disease
Dumont, M., & Beal, M. F. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.11.026 · Cited by 402 · see citing works
Oxidative Stress Signaling in Alzheimers Disease
Su, B., Wang, X., Nunomura, A., Moreira, P., Lee, H.-G., Perry, G., Smith, M., & Zhu, X. (2008) · Current Alzheimer Research · doi:10.2174/156720508786898451 · Cited by 344 · see citing works
Self-citationDepletion of GGA3 Stabilizes BACE and Enhances β-Secretase Activity
Tesco, G., Koh, Y. H., Kang, E. L., Cameron, A. N., Das, S., Sena-Esteves, M., Hiltunen, M., Yang, S.-H., Zhong, Z., Shen, Y., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.012 · Cited by 337 · see citing works
Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation
Leuner, K., Schütt, T., Kurz, C., Eckert, S. H., Schiller, C., Occhipinti, A., Mai, S., Jendrach, M., Eckert, G. P., Kruse, S. E., et al. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4173 · Cited by 354 · see citing works
Di Domenico, F., Tramutola, A., & Butterfield, D. A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.10.490 · Cited by 253 · see citing works
Danger-associated molecular patterns in Alzheimer’s disease
Venegas, C., & Heneka, M. T. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.3mr0416-204r · Cited by 236 · see citing works
Zhong, Z., Ewers, M., Teipel, S., Bürger, K., Wallin, A., Blennow, K., He, P., McAllister, C., Hampel, H., & Shen, Y. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.6.718 · Cited by 206 · see citing works
Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease
Cioffi, F., Adam, R. H. I., & Broersen, K. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190863 · Cited by 204 · see citing works
“In human SK-N-BE neuroblastoma cells, which were exposed to HNE- or H2O2mediated oxidative stress, an increase in A level was found that could be attributed indirectly to - secretase in a c-jun N-terminal kinase (JNK)/c-jun pathway/BACE1 dependent manner [75].”
BackgroundInfluentialSoluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation
Obregon, D., Hou, H., Deng, J., Giunta, B., Tian, J., Darlington, D., Shahaduzzaman, M., Zhu, Y., Mori, T., Mattson, M. P., et al. (2012) · Nature Communications · doi:10.1038/ncomms1781 · Cited by 192 · see citing works
Inhibition of mitochondrial fragmentation protects against Alzheimer’s disease in rodent model
Wang, W., Yin, J., Ma, X., Zhao, F., Siedlak, S. L., Wang, Z., Torres, S., Fujioka, H., Xu, Y., Perry, G., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx299 · Cited by 175 · see citing works
Self-citationCurrent Concepts of Neurodegenerative Mechanisms in Alzheimer’s Disease
Magalingam, K. B., Radhakrishnan, A., Ping, N. S., & Haleagrahara, N. (2018) · BioMed Research International · doi:10.1155/2018/3740461 · Cited by 178 · see citing works
Chami, L., & Checler, F. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-52 · Cited by 168 · see citing works
Obesity, leptin, and Alzheimer's disease
Lee, E. B. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06274.x · Cited by 126 · see citing works
Young, M. L., & Franklin, J. L. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.103409 · Cited by 120 · see citing works
Vascular and metabolic dysfunction in Alzheimer’s disease: a review
Murray, I. V. J., Proza, J. F., Sohrabji, F., & Lawler, J. M. (2011) · Experimental Biology and Medicine · doi:10.1258/ebm.2011.010355 · Cited by 104 · see citing works
p53 at the crossroads between cancer and neurodegeneration
Lanni, C., Racchi, M., Memo, M., Govoni, S., & Uberti, D. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.02.034 · Cited by 95 · see citing works
Croze, M. L., & Zimmer, L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170857 · Cited by 78 · see citing works
Tan, J.-L., Li, Q.-X., Ciccotosto, G. D., Crouch, P. J., Culvenor, J. G., White, A. R., & Evin, G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061246 · Cited by 66 · see citing works
Depletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1
Walker, K. R., Kang, E. L., Whalen, M. J., Shen, Y., & Tesco, G. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5491-11.2012 · Cited by 66 · see citing works
Nutritional interventions for Alzheimer's prevention: a clinical precision medicine approach
Schelke, M. W., Hackett, K., Chen, J. L., Shih, C., Shum, J., Montgomery, M. E., Chiang, G. C., Berkowitz, C., Seifan, A., Krikorian, R., et al. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13070 · Cited by 51 · see citing works
Zhang, Q.-G., Wang, R.-M., Scott, E., Han, D., Dong, Y., Tu, J.-Y., Yang, F., Reddy Sareddy, G., Vadlamudi, R. K., & Brann, D. W. (2013) · Brain · doi:10.1093/brain/awt046 · Cited by 50 · see citing works
Walia, V., Kaushik, D., Mittal, V., Kumar, K., Verma, R., Parashar, J., Akter, R., Rahman, M. H., Bhatia, S., Al-Harrasi, A., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-021-02617-1 · Cited by 47 · see citing works
Transcriptional and post‐transcriptional regulation of β‐secretase
Tamagno, E., Guglielmotto, M., Monteleone, D., Vercelli, A., & Tabaton, M. (2012) · IUBMB Life · doi:10.1002/iub.1099 · Cited by 40 · see citing works
Self-citationBiological and Computational Evaluation of Resveratrol Inhibitors against Alzheimer's Disease
Koukoulitsa, C., Villalonga-Barber, C., Csonka, R., Alexi, X., Leonis, G., Dellis, D., Hamelink, E., Belda, O., Steele, B. R., Micha-Screttas, M., et al. (2016) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.3109/14756366.2014.1003928 · Cited by 37 · see citing works
Kim, W., Ma, L., Lomoio, S., Willen, R., Lombardo, S., Dong, J., Haydon, P. G., & Tesco, G. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0239-7 · Cited by 32 · see citing works
- Authors
- Tamagno, E., Parola, M., Bardini, P., Piccini, A., Borghi, R., Guglielmotto, M., Santoro, G., Davit, A., Danni, O., Smith, M. A., Perry, G., & Tabaton, M.
- Affiliations
- University of Turin (IT)
- University of Genoa (IT)
- Case Western Reserve University (US)
- Corresponding author
- Tamagno, Elena
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2005-01-10
- Volume
- 92
- Issue
- 3
- Pages
- 628-636
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1983730442
- Cited by
- 324
- References
- 3
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 9 · 2023: 15 · 2022: 13 · 2021: 7 · 2020: 17 · 2019: 20 · 2018: 15 · 2017: 12 · 2016: 15 · 2015: 17 · 2014: 11 · 2013: 19 · 2012: 28
- FWCI
- 11.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Ministero dell'Università e della Ricerca
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- 4-hydroxynonenal, BACE1, amyloid-beta, c-Jun N-terminal kinase, p38 MAPK, lipid peroxidation, oxidative stress, Alzheimer's disease, APP processing, apoptosis, caspase-3, STAT
- MeSH terms
- Aldehydes, Cell Line, DNA-Binding Proteins, Humans, Neurons, Endopeptidases, Proto-Oncogene Proteins, Signal Transduction, Trans-Activators, Up-Regulation, Aspartic Acid Endopeptidases, Apoptosis, Protein Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases, Enzyme Activators, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, STAT1 Transcription Factor, Proto-Oncogene Proteins c-akt, Amyloid Precursor Protein Secretases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
