Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6
Open accessAbstract
Background Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a promising drug target for the treatment of Alzheimer's disease. Prolonged BACE1 inhibition interferes with structural and functional synaptic plasticity in mice, most likely by altering the metabolism of BACE1 substrates. Seizure protein 6 (SEZ6) is predominantly cleaved by BACE1, and Sez6 knockout mice share some phenotypes with BACE1 inhibitor–treated mice. We investigated whether SEZ6 is involved in BACE1 inhibition–induced structural and functional synaptic alterations. Methods The function of NB-360, a novel blood-brain barrier penetrant and orally available BACE1 inhibitor, was verified by immunoblotting. In vivo microscopy was applied to monitor the impact of long-term pharmacological BACE1 inhibition on dendritic spines in the cerebral cortex of constitutive and conditional Sez6 knockout mice. Finally, synaptic functions were characterized using electrophysiological field recordings in hippocampal slices. Results BACE1 enzymatic activity was strongly suppressed by NB-360. Prolonged NB-360 treatment caused a reversible spine density reduction in wild-type mice, but it did not affect Sez6 –/– mice. Knocking out Sez6 in a small subset of mature neurons also prevented the structural postsynaptic changes induced by BACE1 inhibition. Hippocampal long-term potentiation was decreased in both chronic BACE1 inhibitor–treated wild-type mice and vehicle-treated Sez6 –/– mice. However, chronic NB-360 treatment did not alter long-term potentiation in CA1 neurons of Sez6 –/– mice. Conclusions Our results suggest that SEZ6 plays an important role in maintaining normal dendritic spine dynamics. Furthermore, SEZ6 is involved in BACE1 inhibition–induced structural and functional synaptic alterations.
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The failure of BACE inhibition trials to demonstrate beneficial effects is thought to be due to effects on other neuronal BACE substrates such as SEZ6.
“which is thought to be due to the effects on other neuronal BACE substrates such as SEZ6 [54]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [54]
The Discussion reports that disrupting SEZ6 function contributes to BACE1 inhibition-induced synaptic alterations in mice. The paper does not establish that this mechanism explains why BACE-inhibition trials failed to show clinical benefit; it says whether similar treatment deficits occur in humans remains unknown (introductory text indexed under Abstract; page unavailable). (LLM, conf=0.86)
Experimental — accuracy not yet measuredPrevious trials to reduce amyloid beta through BACE inhibition have failed to demonstrate similar beneficial effects.
“Previous trials to reduce Aβ through BACE inhibition have failed to demonstrate similar beneficial effects”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [54]
The Discussion reports disappointing outcomes for γ-secretase inhibitor trials, not BACE inhibitor trials. It describes BACE1 inhibitors as under clinical investigation and reports synaptic effects in mice, but does not say that previous BACE inhibitor trials failed to show clinical benefit (pages not provided in our copy). (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn mouse brain, soluble SEZ6 is almost exclusively produced by BACE1.
“In the mouse brain, soluble SEZ6 is almost exclusively produced by BACE1 (1,71).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [1]
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“Previous trials to reduce A β through BACE inhibition have failed to demonstrate similar beneficial effects, which is thought to be due to the effects on other neuronal BACE substrates such as SEZ6 [54], which, importantly, is not expressed in oligodendrocytes ( S16 Fig ).”
Background
- Authors
- Zhu, K., Xiang, X., Filser, S., Marinković, P., Dorostkar, M. M., Crux, S., Neumann, U., Shimshek, D. R., Rammes, G., Haass, C., Lichtenthaler, S. F., Gunnersen, J. M., & Herms, J.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Ludwig-Maximilians-Universität München (DE)
- Novartis Institutes for BioMedical Research (CH)
- TUM Klinikum (DE)
- The University of Melbourne (AU)
- Corresponding author
- Herms, Jochen
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 83
- Issue
- 5
- Pages
- 428-437
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2564588209
- Cited by
- 107
- References
- 63
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 10 · 2023: 11 · 2022: 9 · 2021: 17 · 2020: 11 · 2019: 19 · 2018: 11 · 2017: 4
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
- mediaTUM (Technical University of Munich) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- The Novartis Repository (Novartis) (submittedVersion)
- DZNE Pub (submittedVersion, other-oa)
- Funders
- F. Hoffmann-La Roche
- China Scholarship Council
- Medical Research Council
- National Health and Medical Research Council (1008046, 1058672)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- BACE1 inhibition, BACE1, SEZ6, synaptic plasticity, dendritic spines, Alzheimer's disease, long-term potentiation, hippocampus
- MeSH terms
- Animals, Hippocampus, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neuronal Plasticity, Aspartic Acid Endopeptidases, Long-Term Potentiation, Mice, Knockout, Dendritic Spines, 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 ›
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