Presynaptic α-Synuclein Aggregates, Not Lewy Bodies, Cause Neurodegeneration in Dementia with Lewy Bodies
Open accessAbstract
Lewy bodies, the pathological hallmark of dementia with Lewy bodies (DLB), are large juxtanuclear inclusions of aggregated α-synuclein. However, the small number of cortical Lewy bodies relative to the total neuron count does not correlate with the extent of cognitive impairment. In contrast to dopaminergic neurons in Parkinson's disease, nerve cell loss is usually less prevalent in the cortex of DLB, suggesting a different mechanism of neurodegeneration. Because antibodies used for immunodetection per se do not generally differentiate the aggregated from the physiological and monomeric isoform of α-synuclein, we developed the paraffin-embedded tissue (PET) blot and the protein aggregate filtration (PAF) assay for the sensitive and selective detection of α-synuclein aggregates in tissue slides and brain homogenates, respectively. In contrast to common immunohistochemistry, the PET blot detected an enormous number of small α-synuclein aggregates, which, in contrast to the few Lewy bodies, may explain the cognitive impairment in DLB. Using the PAF assay, we demonstrate that the absolute majority of α-synuclein aggregates are located at presynaptic terminals, suggesting a severe pathological impact on synaptic function. Indeed, parallel to the massive presynaptic accumulation of α-synuclein aggregates, we observed significant synaptic pathology with almost complete loss of dendritic spines at the postsynaptic area. Our results provide strong evidence for a novel concept of neurodegeneration for DLB in which synaptic dysfunction is caused by presynaptic accumulation of α-synuclein aggregates. This concept may also be valid for Parkinson's disease.
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The difference in correlation between CSF NPTX2 and serum GFAP might result from PDD and DLB being Lewy body diseases characterized by α-synuclein accumulations, while AD and FTD are caused by the accumulation of different proteins leading to distinct pathological mechanisms.
“This difference might result from PDD and DLB being Lewy body diseases characterized by α-synuclein accumulations, as indicated above [71, 72], while AD and FTD are caused by the accumulation of different proteins leading to distinct pathological mechanisms.”
Decreased NPTX2 levels in DLB correlate with α-synuclein, confirming possible interaction of α-synuclein aggregates that disturb pre-synaptic functioning when NPTX2 levels are decreased.
“We and others recently showed that decreased NPTX2 levels in DLB correlate with α-synuclein, confirming the possible interaction of α-synuclein aggregates that disturb pre-synaptic functioning when NPTX2 levels are decreased [71, 72].”
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- Authors
- Kramer, M. L., & Schulz-Schaeffer, W. J.
- Affiliations
- University of Göttingen (DE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-02-07
- Volume
- 27
- Issue
- 6
- Pages
- 1405-1410
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6673583
- OpenAlex
- W2145294211
- Cited by
- 571
- References
- 29
- Citations by year
- 2026: 16 · 2025: 31 · 2024: 34 · 2023: 25 · 2022: 30 · 2021: 29 · 2020: 36 · 2019: 31 · 2018: 28 · 2017: 24 · 2016: 40 · 2015: 31 · 2014: 31 · 2013: 23 · 2012: 29
- FWCI
- 22.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Funders
- Volkswagen Foundation (ZN 1294)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- dementia with Lewy bodies, alpha-synuclein aggregates, Lewy bodies, presynaptic terminals, synaptic dysfunction, dendritic spine loss, neurodegeneration, cognitive impairment, Parkinson's disease
- MeSH terms
- Inclusion Bodies, Centrifugation, Density Gradient, Dendrites, Filtration, Frontal Lobe, Humans, Nerve Degeneration, Synaptic Transmission, Synaptosomes, Paraffin Embedding, Lewy Bodies, Presynaptic Terminals, Lewy Body Disease, alpha-Synuclein
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