Convergence of pathology in dementia with Lewy bodies and Alzheimer’s disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease
Open accessAbstract
A growing number of PSEN1 mutations have been associated with dementia with Lewy bodies and familial Alzheimer's disease with concomitant α-synuclein pathology. The objective of this study was to determine if PSEN1 plays a direct role in the development of α-synuclein pathology in these diseases. Using mass spectrometry, immunoelectron microscopy and fluorescence lifetime image microscopy based on Forster resonance energy transfer (FLIM-FRET) we identified α-synuclein as a novel interactor of PSEN1 in wild-type mouse brain tissue. The interaction of α-synuclein with PSEN1 was detected in post-mortem brain tissue from cognitively normal cases and was significantly increased in tissue from cases with dementia with Lewy bodies and familial Alzheimer's disease associated with known PSEN1 mutations. We confirmed an increased interaction of PSEN1 and α-synuclein in cell lines expressing well characterized familial Alzheimer's disease PSEN1 mutations, L166P and delta exon 9, and demonstrated that PSEN1 mutations associate with increased membrane association and accumulation of α-synuclein. Our data provides evidence of a molecular interaction of PSEN1 and α-synuclein that may explain the clinical and pathophysiological overlap seen in synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and some forms of Alzheimer's disease.
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Winslow and colleagues described a novel molecular interaction between PS1 and αSyn.
“A direct involvement of αSyn in the production of Aβ (Fig. 2) in humans could be suggested by results from Winslow and colleagues who described a novel molecular interaction between presenilin 1 (PS1), an important player in the proteolytic processing of the APP to yield Aβ [200], and αSyn [201].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [201]
Complexes of αSyn and PS1 were increased in AD and DLB patients with associated PSEN1 mutations.
“Complexes of αSyn and PS1 where increased in AD and DLB patients with associated PSEN1 mutations [201].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [201]
Results from Winslow and colleagues suggest a direct involvement of αSyn in the production of Aβ in humans.
“A direct involvement of αSyn in the production of Aβ (Fig. 2) in humans could be suggested by results from Winslow and colleagues who described a novel molecular interaction between presenilin 1 (PS1), an important player in the proteolytic processing of the APP to yield Aβ [200], and αSyn [201].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [201]
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α-synuclein in the pathophysiology of Alzheimer’s disease
Twohig, D., & Nielsen, H. M. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0320-x · Cited by 374 · see citing works
The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease
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- Authors
- Winslow, A. R., Moussaud, S., Zhu, L., Post, K. L., Dickson, D. W., Berezovska, O., & McLean, P. J.
- Affiliations
- Harvard University (US)
- Mayo Clinic in Florida (US)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-05-24
- Volume
- 137
- Issue
- 7
- Pages
- 1958-1970
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4065023
- OpenAlex
- W2170496994
- Cited by
- 48
- References
- 53
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 5 · 2019: 7 · 2018: 2 · 2017: 3 · 2016: 8 · 2015: 5
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01AG015379, AG16574-15, AG15379, T32AG023480, P50AG016574)
- National Institute of Neurological Disorders and Stroke (R01NS073740, R01NS063963, P50NS072187)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- dementia with Lewy bodies, Alzheimer's disease, alpha-synuclein, presenilin 1, PSEN1 mutations, familial Alzheimer's disease, synucleinopathies, protein-protein interaction, Parkinson's disease
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cells, Cultured, Cerebral Cortex, Cricetulus, Female, Glutathione Transferase, Humans, Male, Mutation, Neurons, Microscopy, Immunoelectron, CHO Cells, Mice, Knockout, Lewy Body Disease, Mice, alpha-Synuclein, Presenilin-1, Amyloid Precursor Protein Secretases
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