Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid β production
Open accessAbstract
BACKGROUND: Alzheimer's disease (AD)-linked protein, presenilin 1 (PS1), is present at the synapse, and the knock-out of presenilin in mice leads to synaptic dysfunction. On the other hand, synaptic activity was shown to influence PS1-dependent generation of distinct amyloid β (Aβ) species. However, the precise nature of these regulations remains unclear. The current study reveals novel role of PS1 at the synapse, and deciphers how PS1 and synaptic vesicle-associated protein, synaptotagmin 1 (Syt1) modulate each other functions in neurons via direct activity-triggered interaction. Additionally, the therapeutic potential of fostering PS1-Syt1 binding is investigated as a synapse-specific strategy for AD prevention. METHODS: PS1-based cell-permeable peptide targeting PS1-Syt1 binding site was designed to inhibit PS1-Syt1 interaction in neurons. PS1 conformation, synaptic vesicle exocytosis and trafficking were assayed by fluorescence lifetime imaging microscopy (FLIM), glutamate release/synaptopHluorin assay, and fluorescence recovery after photobleaching, respectively. Syt1 level and interaction with PS1 in control and sporadic AD brains were determined by immunohistochemistry and FLIM. AAV-mediated delivery of Syt1 into mouse hippocampi was used to investigate the therapeutic potential of strengthening PS1-Syt1 binding in vivo. Statistical significance was determined using two-tailed unpaired Student's t-test, Mann-Whitney's U-test or two-way ANOVA followed by a Bonferroni's post-test. RESULTS: We demonstrate that targeted inhibition of the PS1-Syt1 binding in neurons, without changing the proteins' expression level, triggers "pathogenic" conformational shift of PS1, and consequent increase in the Aβ42/40 ratio. Moreover, our data indicate that PS1, by binding directly to Syt1, regulates synaptic vesicle trafficking and facilitates exocytosis and neurotransmitter release. Analysis of human brain tissue revealed that not only Syt1 levels but also interactions between remaining Syt1 and PS1 are diminished in sporadic AD. On the other hand, overexpression of Syt1 in mouse hippocampi was found to potentiate PS1-Syt1 binding and promote "protective" PS1 conformation. CONCLUSIONS: The study reports novel functions of PS1 and Syt1 at the synapse, and demonstrates the importance of PS1-Syt1 binding for exocytosis and safeguarding PS1 conformation. It suggests that reduction in the Syt1 level and PS1-Syt1 interactions in AD brain may present molecular underpinning of the pathogenic PS1 conformation, increased Aβ42/40 ratio, and impaired exocytosis.
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SYT1 was found to have reduced abundance in AD.
“The second protein on the list, SYT1, was found to have reduced abundance in AD39.”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [39]
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- Authors
- Zoltowska, K. M., Maesako, M., Lushnikova, I., Takeda, S., Keller, L. J., Skibo, G., Hyman, B. T., & Berezovska, O.
- Affiliations
- Harvard University (US)
- National Academy of Sciences of Ukraine (UA)
- Corresponding author
- Berezovska, Oksana
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2017-02-13
- Volume
- 12
- Issue
- 1
- Pages
- 15-15
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC5307796
- OpenAlex
- W2588474297
- Cited by
- 36
- References
- 83
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 3
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (AG15379, AG044486)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- presenilin 1, synaptotagmin-1, Alzheimer's disease, synaptic vesicle exocytosis, neurotransmitter release, synaptic vesicle trafficking, cell-permeable peptide, hippocampus, sporadic Alzheimer's disease, synapses
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Exocytosis, Humans, Immunohistochemistry, Mice, Inbred C57BL, Neurons, Synapses, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Synaptotagmin I, Presenilin-1, 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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