Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport
Open accessAbstract
The two pathological hallmarks of Alzheimer's disease, amyloid plaques and neurofibrillary tangles, involve two apparently unrelated proteins, the amyloid precursor protein (APP) and Tau. Although it is known that aberrant processing of APP is associated with Alzheimer's disease, the definitive role of APP in neurons is not yet clear. Tau regulates microtubule stabilization and assembly in axons and is, thus, an essential component of the microtubule-associated organelle transport machinery. Although several groups have reported physical interaction between APP and Tau, and induction of Tau phosphorylation by APP and beta-amyloid peptide, the functional connection between APP and Tau is unclear. To explore the possibility that the functions of these two proteins may somehow converge on the same cellular process, we overexpressed APPL, the Drosophila homologue of APP, along with Tau in Drosophila neurons. Panneural coexpression of APPL and Tau resulted in adults that, upon eclosion, failed to expand wings and harden the cuticle, which is suggestive of neuroendocrine dysfunction. We analyzed axonal transport when Tau and APPL were coexpressed and found that transport of axonal cargo was disrupted, as evidenced by increased retention of synaptic proteins in axons and scarcity of neuropeptide-containing vesicles in the distal processes of peptidergic neurons. In an independent approach, we demonstrated genetic interaction and phenotypic similarity between APPL overexpression and…
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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 [30]
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 [30]
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 [30]
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- Authors
- Torroja, L., Chu, H., Kotovsky, I., & White, K.
- Affiliations
- Brandeis University (US)
- Corresponding author
- White, Kalpana
- ORCID
- Torroja, Laura
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 1999-05
- Volume
- 9
- Issue
- 9
- Pages
- 489-493
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2041581676
- Cited by
- 203
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 12 · 2015: 12 · 2014: 9 · 2013: 6 · 2012: 11
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM-22350)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- APPL, amyloid precursor protein, tau protein, axonal transport, Alzheimer's disease, Drosophila neurons, kinesin heavy chain, neuroendocrine dysfunction, genetic interactions
- MeSH terms
- Animals, Axons, Biological Transport, Drosophila, Male, Membrane Proteins, Mice, Transgenic, Microtubules, Nerve Tissue Proteins, Neurons, Gene Expression, Amyloid beta-Protein Precursor, tau Proteins, Drosophila Proteins, Mice
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