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Lewy Bodies Contain Altered α-Synuclein in Brains of Many Familial Alzheimer's Disease Patients with Mutations in Presenilin and Amyloid Precursor Protein Genes
Open accessAbstract
Missense mutations in the alpha-synuclein gene cause familial Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD). To determine whether alpha-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-, and gamma-synuclein. LBs were detected with alpha- but not beta- or gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, alpha-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of alpha-synuclein was reduced compared with control brains. The presence of alpha-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.
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“two studies have shown that individuals with PSEN1 mutations have increased, yet heterogeneous limbic LRP [22, 25].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [22]
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“co-morbid αSyn pathology has been reported in more than half of all autopsy-confirmed AD cases [22–24]”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [22]
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“co-morbid αSyn pathology has been reported in more than half of all autopsy-confirmed AD cases [22–24]”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [22]
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Metadata
- Authors
- Lippa, C. F., Fujiwara, H., Mann, D. M. A., Giasson, B., Baba, M., Schmidt, M. L., Nee, L. E., O'Connell, B., Pollen, D. A., St. George-Hyslop, P., Ghetti, B., Nochlin, D., Bird, T. D., Cairns, N. J., Lee, V. M.-Y., Iwatsubo, T., & Trojanowski, J. Q.
- Affiliations
- The University of Tokyo (JP)
- University of Manchester (GB)
- University of Pennsylvania (US)
- National Institute of Neurological Disorders and Stroke (US)
- University of Massachusetts Chan Medical School (US)
- Indiana University Hospital (US)
- University of Washington (US)
- Corresponding author
- Lippa, Carol F.
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 1998-11
- Volume
- 153
- Issue
- 5
- Pages
- 1365-1370
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1853391
- OpenAlex
- W2066155243
- Cited by
- 533
- References
- 35
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 23 · 2023: 16 · 2022: 19 · 2021: 21 · 2020: 19 · 2019: 17 · 2018: 16 · 2017: 9 · 2016: 11 · 2015: 13 · 2014: 25 · 2013: 13 · 2012: 11
- FWCI
- 17.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7r29ag013623-06)
- National Institute on Aging (P30AG010133, AG09215, U01AG006781, AG13623, P30AG010124, P01AG009215, AG-10124, P50AG005136)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Lewy bodies, alpha-synuclein, familial Alzheimer's disease, presenilin mutations, amyloid precursor protein mutations, amygdala, alpha-synuclein aggregation, protein insolubility, immunoelectron microscopy
- MeSH terms
- Adult, Aged, Alzheimer Disease, Brain, Female, Humans, Immunohistochemistry, Male, Membrane Proteins, Middle Aged, Mutation, Nerve Tissue Proteins, Blotting, Western, Microscopy, Immunoelectron, Amyloid beta-Protein Precursor, Lewy Bodies, Synucleins, alpha-Synuclein, gamma-Synuclein, Presenilin-1
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