ArticleActa neuropathologica communications2016
Super-resolution microscopy reveals γ-secretase at both sides of the neuronal synapse.
Article in Acta neuropathologica communications, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 58 citations in OpenAlex.
- Interferometric ultra-high resolution 3D imaging through brain sections.Nature communications · 2026Article
- The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons.bioRxiv : the preprint server for biology · 2026Article
- Article
- Celebrating the Birthday of AMPA Receptor Nanodomains: Illuminating the Nanoscale Organization of Excitatory Synapses with 10 Nanocandles.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Review
- Advancements and Practical Considerations for Biophysical Research: Navigating the Challenges and Future of Super-resolution Microscopy.Chemical & biomedical imaging · 2024Review
- Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.bioRxiv : the preprint server for biology · 2024Article
- The interwoven fibril-like structure of amyloid-beta plaques in mouse brain tissue visualized using super-resolution STED microscopy.Cell & bioscience · 2023Article
- Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology.Neuroscience bulletin · 2023Review
- Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer's Disease.International journal of molecular sciences · 2023Article
- Bringing synapses into focus: Recent advances in synaptic imaging and mass-spectrometry for studying synaptopathy.Frontiers in synaptic neuroscience · 2023Review
- The epilepsy-associated protein PCDH19 undergoes NMDA receptor-dependent proteolytic cleavage and regulates the expression of immediate-early genes.Cell reports · 2022Article
- Monitoring Various Bioactivities at the Molecular, Cellular, Tissue, and Organism Levels via Biological Lasers.Sensors (Basel, Switzerland) · 2022Review
- Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations.International journal of molecular sciences · 2021Article
- Super-resolution microscopy: a closer look at synaptic dysfunction in Alzheimer disease.Nature reviews. Neuroscience · 2021Review
- Digging Deeper: Advancements in Visualization of Inhibitory Synapses in Neurodegenerative Disorders.International journal of molecular sciences · 2021Review
- Nanoscale organization of Nicastrin, the substrate receptor of the γ-secretase complex, as independent molecular domains.Molecular brain · 2021Article
- Review
- Alteration in synaptic nanoscale organization dictates amyloidogenic processing in Alzheimer's disease.iScience · 2021Article
- A Super-Resolved View of the Alzheimer's Disease-Related Amyloidogenic Pathway in Hippocampal Neurons.Journal of Alzheimer's disease : JAD · 2021Article
- Light Sheet Illumination for 3D Single-Molecule Super-Resolution Imaging of Neuronal Synapses.Frontiers in synaptic neuroscience · 2021Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The transmembrane protein assembly γ-secretase is a key protease in regulated intramembrane processing (RIP) of around 100 type-1 transmembrane proteins. Importantly, it has a pathological role in Alzheimer disease (AD) as it generates the neurotoxic amyloid β-peptide from the amyloid precursor protein (APP). Studies on γ-secretase location are therefore crucial both from a biological and a therapeutic perspective. Despite several years of efforts in many laboratories, it is not clear where in the neuron γ-secretase exerts it's activities. Technical challenges include the fact that the active enzyme contains four protein components and that most subcellular compartments cannot be spatially resolved by traditional light microscopy. Here, we have used a powerful combination of the two nanoscopy techniques STORM and STED microscopy to visualize the location of γ-secretase in neurons using an active-site specific probe, with a focus on the synapse. We show that γ-secretase is present in both the pre-and postsynaptic compartments. We further show that the enzyme is enriched very close to the synaptic cleft in the postsynaptic membrane, as well as to NMDA receptors, demonstrating that γ-secretase is present in the postsynaptic plasma membrane. Importantly, the expression of γ-secretase increased in the pre- and postsynaptic compartments with the size of the synapse, suggesting a correlation between γ-secretase activity and synapse maturation. Thus, our data shows the synaptic location with high precision in three dimensions and settles the long-lasting debate on the synaptic location of γ-secretase.
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