Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila
Open accessAbstract
We tested the hypothesis that amyloid precursor protein (APP) and its relatives function as vesicular receptor proteins for kinesin-I. Deletion of the Drosophila APP-like gene (Appl) or overexpression of human APP695 or APPL constructs caused axonal transport phenotypes similar to kinesin and dynein mutants. Genetic reduction of kinesin-I expression enhanced while genetic reduction of dynein expression suppressed these phenotypes. Deletion of the C terminus of APP695 or APPL, including the kinesin binding region, disrupted axonal transport of APP695 and APPL and abolished the organelle accumulation phenotype. Neuronal apoptosis was induced only by overexpression of constructs containing both the C-terminal and Abeta regions of APP695. We discuss the possibility that axonal transport disruption may play a role in the neurodegenerative pathology of Alzheimer's disease.
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Overexpression of WT APP or APP bearing FAD mutations in Drosophila and mice can cause impaired axonal transport and axonal defects.
“Intriguingly, recent work revealed that overexpression of WT APP or APP bearing FAD mutations in Drosophila and mice can cause impaired axonal transport and axonal defects (7,8,29,30).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [29]
Axonal blockages in Drosophila and mice are thought to correspond to aberrant accumulations of proteins, vesicles and organelles within axons that block or otherwise inhibit normal axonal transport.
“Axonal blockages in Drosophila and mice are thought to correspond to aberrant accumulations of proteins, vesicles and organelles within axons that block or otherwise inhibit normal axonal transport (7,29,(48)(49)(50)(51).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [29]
Overexpression of WT and FAD mutant human APP and Drosophila APPL in the Drosophila larval nervous system causes axonal blockages reminiscent of those found in mutants for molecular motors.
“Previous work showed that overexpression of WT and FAD mutant human APP and Drosophila APPL in the Drosophila larval nervous system causes axonal blockages reminiscent of those found in mutants for molecular motors (29,30,50).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [29]
Expression of the Swedish mutant of APP could induce apoptosis in Drosophila larval neurons.
“In previous work (29), we found that the expression of the Swedish mutant of APP could induce apoptosis in Drosophila larval neurons.”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [29]
In both Drosophila and mice, APP-mediated axonal transport defects can be enhanced by genetic reductions in kinesin-I.
“In fact, in both Drosophila and mice, APP-mediated axonal transport defects can be enhanced by genetic reductions in kinesin-I (7,29,30).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [29]
Expression of human APP carrying the Swedish FAD mutation caused axonal blockages within larval segmental nerves.
“In previous work, we found that the expression of human APP carrying the Swedish FAD mutation caused axonal blockages within larval segmental nerves (29).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [29]
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References 56 · Cited by 428
- Authors
- Gunawardena, S., & Goldstein, L. S. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Goldstein, Lawrence S.B.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2001-11
- Volume
- 32
- Issue
- 3
- Pages
- 389-401
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2065384834
- Cited by
- 428
- References
- 56
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 10 · 2023: 9 · 2022: 11 · 2021: 7 · 2020: 13 · 2019: 15 · 2018: 15 · 2017: 10 · 2016: 13 · 2015: 24 · 2014: 23 · 2013: 18 · 2012: 26
- FWCI
- 14.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM 35252, R01GM035252)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- amyloid precursor protein, axonal transport, dynein, APP695, APPL, neuronal viability, neuronal apoptosis, Alzheimer's disease, neurodegeneration, Drosophila
- MeSH terms
- Animals, Axonal Transport, Cell Survival, Drosophila, Humans, Mutation, Neurons, Kinesins, Amyloid beta-Protein Precursor, Cell Death
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