Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic Mice
Open accessAbstract
γ-Secretase inhibitors (GSIs) reduce amyloid-β (Aβ) peptides but inevitably increase the β-C-terminal fragment (β-CTF) of amyloid precursor protein (APP), potentially having undesirable effects on synapses. In contrast, γ-secretase modulators (GSMs) reduce Aβ42 without increasing β-CTF. Although the Aβ-lowering effects of these compounds have been extensively studied, little effort has been made to investigate their effects on cognition. Here, we compared the effects of two GSIs—(2 S)-2-hydroxy-3-methyl-N-[(2 S)-1-{[(1 S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1 H-3-benzazepin-1-yl]amino}-1-oxopropan-2-yl]butanamide (LY450139, semagacestat) and (2 R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxazol-3-yl)phenyl]methyl]amino-5,5,5-trifluoropentanamide (BMS-708163)—and a second-generation GSM [{(2 S,4 R)-1-[(4 R)-1,1,1-trifluoro-7-methyloctan-4-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetic acid (GSM-2)] on spatial working memory in APP-transgenic (Tg2576) and nontransgenic mice using the Y-maze task. While acute dosing with either GSI ameliorated memory deficits in 5.5-month-old Tg2576 mice, these effects disappeared after 8 d subchronic dosing. Subchronic dosing with either GSI rather impaired normal cognition in 3-month-old Tg2576 mice, with no inhibition on the processing of other γ-secretase substrates, such as Notch, N-cadherin, or EphA4, in the brain. LY450139 also impaired normal cognition in wild-type mice; however, the potency was 10-fold lower than that in Tg2576 mice, indicating an APP-dependent mechanism likely with β-CTF accumulation. Immunofluorescence studies revealed that the β-CTF accumulation was localized in the presynaptic terminals of the hippocampal stratum lucidum and dentate hilus, implying an effect on presynaptic function in the mossy fibers. In contrast, both acute and subchronic dosing with GSM-2 significantly ameliorated memory deficits in Tg2576 mice and did not affect normal cognition in wild-type mice. We demonstrated a clear difference between GSI and GSM in effects on functional consequences, providing new insights into strategies for developing these drugs against Alzheimer's disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
The accumulation of β-secretase cleaved fragments of APP has been implicated as mediators of behavioral dysfunction.
“The accumulation of β-secretase cleaved fragments of APP has been implicated as mediators of behavioral dysfunction”
From Normal cognition in transgenic BRI2-Aβ mice (2013) · cites this paper as [54]
Previous studies have shown that aggregated Aβ can interact with APP.
“and previous studies have shown that aggregated Aβ can interact with APP [54-56]”
From Normal cognition in transgenic BRI2-Aβ mice (2013) · cites this paper as [54]
The Introduction says Aβ is produced by cleavage of APP, and the cultured-cell results examine how drugs affect APP processing and Aβ secretion. Neither passage addresses whether aggregated Aβ interacts with APP; searches for that interaction and for Aβ oligomers binding APP found no supporting passage in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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 · cited 2× · see citing works
“The first cleavage by -secretase generates the -C-terminal fragment of APP ( CTF) (otherwise known as C99) (Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999), and the second cleavage is induced by”
BackgroundIwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., & Ihara, Y. (1994) · Neuron · doi:10.1016/0896-6273(94)90458-8 · Cited by 1,774 · see citing works
A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., Findlay, K. A., Smith, T. E., Murphy, M. P., Bulter, T., et al. (2001) · Nature · doi:10.1038/35102591 · Cited by 1,388 · see citing works
Lacor, P. N., Buniel, M. C., Furlow, P. W., Sanz Clemente, A., Velasco, P. T., Wood, M., Viola, K. L., & Klein, W. L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3501-06.2007 · Cited by 1,188 · see citing works
NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., Ozols, V. V., Jessing, K. W., Zavitz, K. H., Koo, E. H., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18162 · Cited by 634 · see citing works
Kuperstein, I., Broersen, K., Benilova, I., Rozenski, J., Jonckheere, W., Debulpaep, M., Vandersteen, A., Segers‐Nolten, I., Van Der Werf, K., Subramaniam, V., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.211 · Cited by 532 · see citing works
Bittner, T., Fuhrmann, M., Burgold, S., Jung, C. K. E., Volbracht, C., Steiner, H., Mitteregger, G., Kretzschmar, H. A., Haass, C., & Herms, J. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2288-09.2009 · Cited by 123 · see citing works
Bot, N., Schweizer, C., Ben Halima, S., & Fraering, P. C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.142521 · Cited by 81 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Single App knock-in mouse models of Alzheimer’s disease
Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S., Iwata, N., & Saido, T. C. (2014) · Nature Neuroscience · doi:10.1038/nn.3697 · Cited by 1,447 · see citing works
APP mouse models for Alzheimer’s disease preclinical studies.
Sasaguri, H., Nilsson, P., Hashimoto, S., Nagata, K., Saito, T., De Strooper, B., Hardy, J., Vassar, R., Winblad, B., & Saido, T. C. (2017) · The EMBO Journal · doi:10.15252/embj.201797397 · Cited by 793 · see citing works
Lessons from a failed γ-secretase Alzheimer trial
De Strooper, B. (2014) · Cell · doi:10.1016/j.cell.2014.10.016 · Cited by 277 · see citing works
Mouse Models of Alzheimer’s Disease
Yokoyama, M., Kobayashi, H., Tatsumi, L., & Tomita, T. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.912995 · Cited by 213 · see citing works
Lauritzen, I., Pardossi-Piquard, R., Bauer, C., Brigham, E., Abraham, J.-D., Ranaldi, S., Fraser, P., St-George-Hyslop, P., Le Thuc, O., Espin, V., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.2775-12.2012 · Cited by 201 · see citing works
“…have shown that -secretase inhibitors leading to strong accumulation of C-terminal fragments (C83 or C99) have undesirable effects on synapses (Bittner et al., 2009) and negatively affect cognitive function in Tg2576 and wild-type mice, when administrated subchronically (Mitani et al., 2012).”
BackgroundMaking the final cut: Pathogenic amyloid-β peptide generation by γ-secretase
Steiner, H., Fukumori, A., Tagami, S., & Okochi, M. (2018) · Cell Stress · doi:10.15698/cst2018.11.162 · Cited by 133 · see citing works
Animal models of Alzheimer disease: historical pitfalls and a path forward
Cavanaugh, S. E. (2014) · ALTEX · doi:10.14573/altex.1310071 · Cited by 132 · see citing works
Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression
Saito, T., Matsuba, Y., Yamazaki, N., Hashimoto, S., & Saido, T. C. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1907-16.2016 · Cited by 121 · see citing works
Zhang, C., Griciuc, A., Hudry, E., Wan, Y., Quinti, L., Ward, J., Forte, A. M., Shen, X., Ran, C., Elmaleh, D. R., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-19641-2 · Cited by 99 · see citing works
Normal cognition in transgenic BRI2-Aβ mice
Kim, J., Chakrabarty, P., Hanna, A., March, A., Dickson, D. W., Borchelt, D. R., Golde, T., & Janus, C. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-15 · Cited by 83 · see citing works
Cao, Q., Shin, W. S., Chan, H., Vuong, C. K., Dubois, B., Li, B., Murray, K. A., Sawaya, M. R., Feigon, J., Black, D. L., et al. (2018) · Nature Chemistry · doi:10.1038/s41557-018-0147-z · Cited by 75 · see citing works
Rogers, K., Felsenstein, K. M., Hrdlicka, L., Tu, Z., Albayya, F., Lee, W., Hopp, S., Miller, M.-J., Spaulding, D., Yang, Z., et al. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-61 · Cited by 75 · see citing works
Turning the tide on Alzheimer’s disease: modulation of γ-secretase
Luo, J. E., & Li, Y.-M. (2022) · Cell & Bioscience · doi:10.1186/s13578-021-00738-7 · Cited by 59 · see citing works
- Authors
- Mitani, Y., Yarimizu, J., Saita, K., Uchino, H., Akashiba, H., Shitaka, Y., Ni, K., & Matsuoka, N.
- Affiliations
- Astellas Pharma (Japan) (JP)
- ORCID
- Uchino, Hiroshi
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-02-08
- Volume
- 32
- Issue
- 6
- Pages
- 2037-2050
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6621706
- OpenAlex
- W2126995971
- Cited by
- 203
- References
- 8
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 8 · 2023: 9 · 2022: 8 · 2021: 11 · 2020: 13 · 2019: 9 · 2018: 10 · 2017: 19 · 2016: 24 · 2015: 16 · 2014: 25 · 2013: 22 · 2012: 16
- FWCI
- 17.80
- 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)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- gamma-secretase inhibitors, γ-secretase modulators, amyloid precursor protein, amyloid-beta, semagacestat, spatial working memory, Tg2576 mice, cognitive impairment, Notch signaling, EphA4, N-cadherin
- MeSH terms
- Alanine, Animals, Azepines, Cognition, Female, Humans, Mice, Transgenic, Protease Inhibitors, Amyloid beta-Protein Precursor, Maze Learning, Cell Line, Tumor, Mice, 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
