APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology
Jin Y, Li F, Sonoustoun B, Kondru NC, Martens YA, Qiao W, Heckman MG, Ikezu TC et al.. Acta neuropathologica, 2022-04-26
Topic: Brain proteins, microglia and lab models
Approximately half of Alzheimer's disease (AD) brains have concomitant Lewy pathology at autopsy, suggesting that α-synuclein (α-SYN) aggregation is a regulated event in the pathogenesis of AD. Genome-wide association studies revealed that the ε4 allele of the apolipoprotein E (APOE4) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying an important role of APOE4 in both amyloid-β (Aβ) and α-SYN pathogenesis. How APOE4 modulates α-SYN aggregation in AD is unclear. In this study, we aimed to determine how α-SYN is associated with AD-related pathology and how APOE4 impacts α-SYN seeding and toxicity. We measured α-SYN levels and their association with other established AD-related markers in brain samples from autopsy-confirmed AD patients (N = 469), where 54% had concomitant LB pathology (AD + LB). We found significant correlations between the levels of α-SYN and those of Aβ40, Aβ42, tau and APOE, particularly in insoluble fractions of AD + LB. Using a real-time quaking-induced conversion (RT-QuIC) assay, we measured the seeding activity of soluble α-SYN and found that α-SYN seeding was exacerbated by APOE4 in the AD cohort, as well as a small cohort of autopsy-confirmed LBD brains with minimal Alzheimer type pathology. We further fractionated the soluble AD brain lysates by size exclusion chromatography (SEC) ran on fast protein liquid chromatography (FPLC) and identified the α-SYN species (~ 96 kDa) that showed the strongest seeding activity. Finally, using human induced pluripotent stem cell (iPSC)-derived neurons, we showed that amplified α-SYN aggregates from AD + LB brain of patients with APOE4 were highly toxic to neurons, whereas the same amount of α-SYN monomer was not toxic. Our findings suggest that the presence of LB pathology correlates with AD-related pathologies and that APOE4 exacerbates α-SYN seeding activity and neurotoxicity, providing mechanistic insight into how APOE4 affects α-SYN pathogenesis in AD.
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APA 7th
Jin, Y., Li, F., Sonoustoun, B., Kondru, N. C., Martens, Y. A., Qiao, W., et al. (2022). APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology. Acta neuropathologica. https://doi.org/10.1007/s00401-022-02421-8
Vancouver
Jin Y, Li F, Sonoustoun B, Kondru NC, Martens YA, Qiao W, et al. APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology. Acta neuropathologica. 2022. doi:10.1007/s00401-022-02421-8. PMID: 35471463.
BibTeX
@article{jin2022-35471463,
author = {Jin, Y. and Li, F. and Sonoustoun, B. and Kondru, N. C. and Martens, Y. A. and Qiao, W. and Heckman, M. G. and Ikezu, T. C. and others},
title = {{APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology}},
journal = {Acta neuropathologica},
year = {2022},
doi = {10.1007/s00401-022-02421-8},
pmid = {35471463},
url = {https://doi.org/10.1007/s00401-022-02421-8}
}
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Key findings
- Approximately half of Alzheimer's disease (AD) brains have concomitant Lewy pathology at autopsy, suggesting that α-synuclein (α-SYN) aggregation is a regulated event in the pathogenesis of AD.
- Genome-wide association studies revealed that the ε4 allele of the apolipoprotein E (APOE4) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying an important role of APOE4 in both amyloid-β (Aβ) and α-SYN pathogenesis.
- In this study, we aimed to determine how α-SYN is associated with AD-related pathology and how APOE4 impacts α-SYN seeding and toxicity.
- We found significant correlations between the levels of α-SYN and those of Aβ40, Aβ42, tau and APOE, particularly in insoluble fractions of AD + LB.
- Finally, using human induced pluripotent stem cell (iPSC)-derived neurons, we showed that amplified α-SYN aggregates from AD + LB brain of patients with APOE4 were highly toxic to neurons, whereas the same amount of α-SYN monomer was not toxic.
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Study details
- Participants469
- Evidence strengthModerate
How this study scored 59/100
Published in a leading specialty journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 34 of the 58 points we could judge it on, which is 59 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 2 / 4 | 469 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 35471463) |
| Free to read | 2 / 2 | Free to read |
| Points | 34 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 34 of the 58 points we could judge it on is 59 out of 100. |
| Total | 59 / 100 | — |
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