Altered Metabolism of the Amyloid β Precursor Protein Is Associated with Mitochondrial Dysfunction in Down's Syndrome
Open accessAbstract
Most Down's syndrome (DS) patients develop Alzheimer's disease (AD) neuropathology. Astrocyte and neuronal cultures derived from fetal DS brain show alterations in the processing of amyloid beta precursor protein (AbetaPP), including increased levels of AbetaPP and C99, reduced levels of secreted AbetaPP (AbetaPPs) and C83, and intracellular accumulation of insoluble Abeta42. This pattern of AbetaPP processing is recapitulated in normal astrocytes by inhibition of mitochondrial metabolism, consistent with impaired mitochondrial function in DS astrocytes. Intracellular Abeta42 and reduced AbetaPPs are also detected in DS and AD brains. The survival of DS neurons is markedly increased by recombinant or astrocyte-produced AbetaPPs, suggesting that AbetaPPs may be a neuronal survival factor. Thus, mitochondrial dysfunction in DS may lead to intracellular deposition of Abeta42, reduced levels of AbetaPPs, and a chronic state of increased neuronal vulnerability.
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In DS and APP transgenics, intraneuronal Aβ accumulation has also been observed before the formation of plaques, suggesting the possibility that build-up of Aβ within neurons may play a role in plaque formation and neurodegeneration.
“In DS and APP transgenics, intraneuronal A 𝛃 accumulation has also been observed before the formation of plaques (Gyure et al., 2001; Busciglio et al., 2002; Oddo et al., 2003; Cataldo et al., 2004; Schmitz et al., 2004), suggesting the possibility that build-up of A 𝛃 within neurons may play a role in plaque formation and neurodegeneration.”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Busciglio et al., 2002
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References 72 · Cited by 387
- Authors
- Busciglio, J., Pelsman, A., Wong, C., Pigino, G., Yuan, M., Mori, H., & Yankner, B. A.
- Affiliations
- UConn Health (US)
- Boston Children's Hospital (US)
- Osaka City University (JP)
- Corresponding author
- Busciglio, Jorge
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2002-02
- Volume
- 33
- Issue
- 5
- Pages
- 677-688
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2121042833
- Cited by
- 387
- References
- 72
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 15 · 2023: 12 · 2022: 11 · 2021: 16 · 2020: 14 · 2019: 19 · 2018: 8 · 2017: 15 · 2016: 12 · 2015: 12 · 2014: 17 · 2013: 17 · 2012: 18
- FWCI
- 14.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns033325-03)
- National Institute of Neurological Disorders and Stroke (R01NS030352, NS33325, NS30352)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-38466, R01HD038466)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Down syndrome, amyloid precursor protein, amyloid-beta processing, mitochondrial dysfunction, Alzheimer's disease, C99, astrocytes, neuronal survival, neuronal vulnerability
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Astrocytes, Benzimidazoles, Carbocyanines, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Cell Survival, Cells, Cultured, Cerebral Cortex, Child, Child, Preschool, Down Syndrome, Fetus, Fluorescent Dyes, Hippocampus, Humans, Immunohistochemistry, Infant, Middle Aged, Mitochondria, Neurons, Peptide Fragments, Recombinant Proteins, Uncoupling Agents, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Apoptosis, In Situ Nick-End Labeling
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