Expression of β-Amyloid Induced Age-Dependent Presynaptic and Axonal Changes in Drosophila
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Alzheimer's disease (AD) is attributable to synapse dysfunction and loss, but the nature and progression of the presynaptic structural and functional changes in AD are essentially unknown. We expressed wild-type or arctic form of β amyloid 1-42(Aβ) in a small group of neurons in the adult fly and performed extensive time course analysis of the function and structure of both axon and presynaptic terminals at the identified single-neuron level. Aβ accumulated intracellularly and induced a range of age-dependent changes, including depletion of presynaptic mitochondria, slowdown of bi-directional transports of axonal mitochondria, decreased synaptic vesicles, increased large vacuoles, and elevated synaptic fatigue. These structural and functional synaptic changes correlated with age-dependent deficit in motor behavior. All these alterations were accelerated in flies expressing the arctic form of Aβ. The depletion of presynaptic mitochondria was the earliest detected phenotype and was not caused by the change in axonal transport of mitochondria. Moreover, axonal mitochondria exhibited a dramatic reduction in number but a significant increase in size in aged Aβ-expressing flies, indicating a global depletion of mitochondria in the neuron and an impairment of mitochondria fission. These results suggest that Aβ accumulation depletes presynaptic and axonal mitochondria, leading to other presynaptic deficits.
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The amyloid hypothesis is supported by early Aβ accumulation in autosomal dominant AD, transgenic mice, and studies suggesting mitochondrial Aβ may cause synaptic degeneration and cognitive impairment.
“This hypothesis is supported by the early Aβ accumulation in the rare, autosomal dominant forms of AD, by transgenic mice harboring these human mutations (Hardy and Selkoe, 2002), and by recent studies suggesting that mitochondrial Aβ may be responsible for synaptic degeneration and the onset of cognitive impairment in AD models of Aβ enrichment (Zhao et al., 2010).”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Zhao et al., 2010
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- Authors
- Zhao, X.-L., Wang, W.-A., Tan, J.-X., Huang, J.-K., Zhang, X., Zhang, B.-Z., Wang, Y.-H., YangCheng, H.-Y., Zhu, H.-L., Sun, X.-J., & Huang, F.-D.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Huang, Fu-De
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-01-27
- Volume
- 30
- Issue
- 4
- Pages
- 1512-1522
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6633795
- OpenAlex
- W1979534447
- Cited by
- 130
- References
- 15
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 10 · 2022: 4 · 2021: 11 · 2020: 12 · 2019: 4 · 2018: 4 · 2017: 7 · 2016: 12 · 2015: 10 · 2014: 9 · 2013: 3 · 2012: 14
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Chinese Academy of Sciences (KSCX2-YW-R)
- National Key Research and Development Program of China (2006CB806600)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- amyloid-beta, Alzheimer's disease, presynaptic terminals, axons, mitochondria, mitochondrial transport, mitochondrial fission, synaptic vesicles, synaptic fatigue, age-related neurodegeneration, Drosophila, synaptic dysfunction
- MeSH terms
- Aging, Animals, Axonal Transport, Central Nervous System, Disease Models, Animal, Drosophila, Energy Metabolism, Mitochondria, Nerve Degeneration, Synaptic Transmission, Synaptic Vesicles, Vacuoles, Wallerian Degeneration, Down-Regulation, Amyloid beta-Peptides, Presynaptic Terminals
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