ArticleMolecular neurodegeneration2016
Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons.
Article in Molecular neurodegeneration, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 120 citations in OpenAlex.
- Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.JAMA neurology · 2021Trial
- Small Molecule Therapeutics Targeting Amyloid-β in Alzheimer's Disease: Mechanisms, Clinical Progress, and Future Strategies.Experimental neurobiology · 2026Review
- GalNAc-T13 maintains neurite architecture and memory retention via O-GalNAc glycosylation of seizure protein 6.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The Association of Environmental Variables with Intelligence and Well-Being in Copy Number Variation (CNV) Carriers.Research square · 2026Article
- Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.Proteomics · 2026Article
- SEZ6L2 Loss Disrupts Motor Coordination, Cognitive Function, and Synaptic Connectivity.bioRxiv : the preprint server for biology · 2026Article
- Sez6l promotes neuropathic pain via Wnt5a/CaFrontiers in genetics · 2026Article
- BACE1 regulates sleep-wake cycle through both enzymatic and non-enzymatic actions.EMBO reports · 2026Article
- Seizure-Related Homolog Protein 6 (SEZ6): Biology and Therapeutic Target in Neuroendocrine Carcinomas.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Review
- Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia.Cell death & disease · 2025Article
- HILAMA: High-dimensional multi-omics mediation analysis with latent confounding.BMC medical research methodology · 2025Article
- Detection of SEZ6, a Therapeutic Target, in Medullary Thyroid Carcinoma.The Journal of clinical endocrinology and metabolism · 2025Article
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- It's good to know what to BACE the specificity of your inhibitors on.The Journal of clinical investigation · 2024Article
- The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.The Journal of clinical investigation · 2024Article
- Associations of CSF BACE1 with amyloid pathology, neurodegeneration, and cognition in Alzheimer's disease.Acta neuropathologica · 2024Article
- A novel mouse model for N-terminal truncated Aβ2-x generation through meprin β overexpression in astrocytes.Cellular and molecular life sciences : CMLS · 2024Article
- New Highly Selective BACE1 Inhibitors and Their Effects on Dendritic Spine Density In Vivo.International journal of molecular sciences · 2023Article
- ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Postnatal neuronal Bace1 deletion impairs neuroblast and oligodendrocyte maturation.Human molecular genetics · 2023Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 9 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe protease BACE1 (beta-site APP cleaving enzyme) is a major drug target in Alzheimer's disease. However, BACE1 therapeutic inhibition may cause unwanted adverse effects due to its additional functions in the nervous system, such as in myelination and neuronal connectivity. Additionally, recent proteomic studies investigating BACE1 inhibition in cell lines and cultured murine neurons identified a wider range of neuronal membrane proteins as potential BACE1 substrates, including seizure protein 6 (SEZ6) and its homolog SEZ6L. METHODS AND
resultsWe generated antibodies against SEZ6 and SEZ6L and validated these proteins as BACE1 substrates in vitro and in vivo. Levels of the soluble, BACE1-cleaved ectodomain of both proteins (sSEZ6, sSEZ6L) were strongly reduced upon BACE1 inhibition in primary neurons and also in vivo in brains of BACE1-deficient mice. BACE1 inhibition increased neuronal surface levels of SEZ6 and SEZ6L as shown by cell surface biotinylation, demonstrating that BACE1 controls surface expression of both proteins. Moreover, mass spectrometric analysis revealed that the BACE1 cleavage site in SEZ6 is located in close proximity to the membrane, similar to the corresponding cleavage site in SEZ6L. Finally, an improved method was developed for the proteomic analysis of murine cerebrospinal fluid (CSF) and was applied to CSF from BACE-deficient mice. Hereby, SEZ6 and SEZ6L were validated as BACE1 substrates in vivo by strongly reduced levels in the CSF of BACE1-deficient mice.
conclusionsThis study demonstrates that SEZ6 and SEZ6L are physiological BACE1 substrates in the murine brain and suggests that sSEZ6 and sSEZ6L levels in CSF are suitable markers to monitor BACE1 inhibition in mice.
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