The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport
Open accessAbstract
The retromer complex plays an important role in intracellular transport, is highly expressed in the hippocampus, and has been implicated in the trafficking of the amyloid precursor protein (APP). Nevertheless, the trafficking routes of the neuronal retromer and the role it plays in APP transport in neuronal processes remain unknown. Here we use hippocampal neuronal cultures to address these issues. Using fluorescence microscopy, we find that Vps35, the core element of the retromer complex, is in dendrites and axons, is enriched in endosomes and trans-Golgi network, and is found in APP-positive vesicles. Next, to identify the role the neuronal retromer plays in cargo transport, we infected hippocampal neurons with a lentivirus expressing shRNA to silence Vps35. By live fluorescence imaging, Vps35 deficiency was found to reduce the frequency, but not the kinetics, of long-range APP transport within neuronal processes. Supporting the interpretation that retromer promotes long-range transport, Vps35 deficiency led to increased APP in the early endosomes, in processes but not the soma. Finally, Vps35 deficiency was associated with increased levels of Aβ, a cleaved product of APP, increased colocalization of APP with its cleaving enzyme BACE1 in processes, and caused an enlargement of early endosomes. Taken together, our studies clarify the function of the neuronal retromer, and suggest specific mechanisms for how retromer dysfunction observed in Alzheimer's disease affects APP transport and processing.
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APP can be cleaved to Aβ when it is trapped in endosomes that contain β-secretase (BACE).
“APP can be cleaved to Aβ (Fig. 5, magenta) when it is trapped in endosomes that contain β-secretase (BACE)143, a process exacerbated by the APOE E4 genotype144,145.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [143]
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- Authors
- Bhalla, A., Vetanovetz, C. P., Morel, E., Chamoun, Z., Di Paolo, G., & Small, S. A.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Small, Scott A.
- ORCID
- Small, Scott A.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 47
- Issue
- 1
- Pages
- 126-134
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC3589992
- OpenAlex
- W1997962857
- Cited by
- 130
- References
- 3
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 11 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 9 · 2019: 11 · 2018: 9 · 2017: 14 · 2016: 12 · 2015: 14 · 2014: 14 · 2013: 4 · 2012: 3
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- The Alzheimer's Association
- NIH grants (AG025161, NS056049)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- retromer complex, VPS35, amyloid precursor protein, neural processes, early endosomes, trans-Golgi network, APP processing, amyloid-beta, BACE1, Alzheimer's disease, hippocampal neurons, freight transport
- MeSH terms
- Alzheimer Disease, Cells, Cultured, Hippocampus, Humans, Neurons, Endosomes, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Protein Transport, trans-Golgi Network, Vesicular Transport Proteins, Amyloid Precursor Protein Secretases
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