Related Experiment Video
Updated: Mar 29, 2026
08:16
Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus
Published on: June 17, 2015
19.4K
Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway
Utpal Das1,2, Lina Wang1,2, Archan Ganguly1,2
1Department of Pathology, University of California, San Diego, La Jolla, California, USA.
Nature Neuroscience
|December 8, 2015
Summary
Researchers visualized amyloid precursor protein (APP) and BACE-1 interactions in neurons using a novel optical assay. This Alzheimer's disease study reveals APP cleavage occurs in multiple cellular compartments, impacting therapeutic strategies.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Amyloid precursor protein (APP) cleavage by BACE-1 is critical for amyloid-β (Aβ) production, a key factor in Alzheimer's disease (AD).
- The precise cellular locations where APP and BACE-1 interact and APP cleavage occurs within neurons remain largely undetermined.
- Understanding these interactions is crucial for developing effective AD therapeutics.
Purpose of the Study:
- To develop and utilize a novel optical assay to visualize APP-BACE-1 interactions in living cells.
- To identify the specific neuronal compartments where APP and BACE-1 converge and APP cleavage takes place.
- To investigate the impact of AD-protective mutations on APP-BACE-1 interactions.
Main Methods:
- Development of a fluorescence complementation-based optical assay for in cellulo visualization of APP-BACE-1 interactions.
- Application of the assay in hippocampal neurons, combined with assays tracking internalized APP.
- Analysis of APP and BACE-1 localization and interaction dynamics in various neuronal compartments.
Main Results:
- APP and BACE-1 were found to interact in both biosynthetic and endocytic pathways within neurons.
- Interactions were particularly prominent in recycling microdomains, including dendritic spines and presynaptic boutons.
- APP and BACE-1 were observed to be cotransported and interact during axonal transit.
- The Icelandic mutation, protective against AD, significantly reduced APP-BACE-1 interactions.
Conclusions:
- Neuronal APP cleavage by BACE-1 occurs in diverse cellular compartments, challenging previous models.
- APP-BACE-1 interactions in both biosynthetic and endocytic pathways are significant for Aβ production.
- The findings provide a mechanistic explanation for the protective effect of the Icelandic mutation.
- The study offers new insights into APP processing and potential therapeutic targets for Alzheimer's disease.
Related Concept Videos
03:03Amyloid Fibrils
12.9K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
12.9K
03:03Amyloid Fibrils
6.9K
6.9K
01:26Alzheimer's Disease: Overview
2.0K
Alzheimer's Disease (AD) is a continually advancing neurodegenerative disorder, distinguished by escalating memory loss, cognitive dysfunction, and dementia. The disease unfolds in three stages: preclinical, mild cognitive impairment (MCI), and dementia. Its onset is insidious, and the progression gradual, with the cause not well explained by other disorders.
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
2.0K
01:13The Proteasome
2.0K
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
2.0K