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A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides
Abstract
Pathogenic aggregates of alpha-synuclein are thought to contribute to the development of Parkinson's disease. Inclusion bodies containing alpha-synuclein are present in Parkinson's disease and other neurodegenerative diseases, including Alzheimer's disease. Moreover, alpha-synuclein mutations are found in cases of familial Parkinson's disease, and transgenic overexpression of alpha-synuclein causes neurodegeneration in mice. The molecular mechanisms involved, however, remain incompletely understood. Here we show that, in transgenic mice, alpha-synuclein induced neurodegeneration involves activation of the ubiquitin/proteasome system, a massive increase in apolipoprotein E (ApoE) levels and accumulation of insoluble mouse Abeta. ApoE was not protective, but was injurious, as deletion of ApoE delayed the neurodegeneration caused by alpha-synuclein and suppressed the accumulation of Abeta. Our data reveal a molecular link between central pathogenic mechanisms implicated in Parkinson's disease and Alzheimer's disease and suggest that intracellular alpha-synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE.
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“Notably, genetic ablation of ApoE in various neurodegenerative mouse models — including tauopathy69, synucleinopathy106, and experimental autoimmune encephalomyelitis (EAE)107 — shows a similar protective effect against neurodegeneration and disease severity”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [106]
In the citing paper
“In a mouse model of Parkinson’s disease featuring synucleinopathy, ApoE deletion significantly attenuates the loss of spinal cord motor neurons, delays disease onset, and improves survival106.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [106]
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Agnello, L., Gambino, C. M., Ciaccio, A. M., Piccoli, T., Blandino, V., Scazzone, C., Sasso, B. L., Ben, F. D., & Ciaccio, M. (2024) · Clinica Chimica Acta · doi:10.1016/j.cca.2024.119876 · Cited by 12
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“Alterations in lipid metabolism have an important role in the pathogenesis of Parkinson’s disease since there is direct cross-talk between lipids and α-synuclein, influencing both lipid metabolism and α-synuclein aggregation.(98,99) In the brain, apolipoprotein E is expressed by astrocytes and perivascular cells under…”
BackgroundShang, S., Chen, Y., Zhang, H., Dou, W., Qian, L., Yin, X., & Wu, J. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00857 · Cited by 8
“Gallardo et al. (2008) found that ApoE ameliorates amyloid-β (Aβ) accumulation and neurodegeneration in a transgenic mouse model of PD and indicated that the interaction of ApoE with distinct neural substrates produced some of the alterations observed in PDD. Nombela et al. (2014) found reduced…”
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“Accumulation of α-synuclein may lead to synaptic loss, perturbation of dopamine storage or release, a massive increase in apolipoproteinE levels and accumulation of insoluble amyloid [84,85].”
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Self-citationTargeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?
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Metadata
- Authors
- Gallardo, G., Schlüter, O. M., & Südhof, T. C.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- European Neuroscience Institute Göttingen (DE)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Gallardo, Gilbert
- Venue
- Nature Neuroscience
- Published
- 2008-02-24
- Volume
- 11
- Issue
- 3
- Pages
- 301-308
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W1564677510
- Cited by
- 145
- References
- 48
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 6 · 2020: 5 · 2019: 10 · 2018: 9 · 2017: 8 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 9 · 2012: 13
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Mental Health (R01MH069585)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, apolipoprotein E, amyloid-beta, Parkinson's disease, Alzheimer's disease, neurodegeneration, ubiquitin-proteasome system, transgenic mice, protein aggregation, extracellular signaling
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Mice, Transgenic, Nerve Degeneration, Parkinson Disease, Peptides, Signal Transduction, Amyloid beta-Peptides, Cell Death, Mice, Knockout, Neurodegenerative Diseases, Lewy Body Disease, Ubiquitin, Proteasome Endopeptidase Complex, Mice, alpha-Synuclein
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