Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs
Parcon PA, Balasubramaniam M, Ayyadevara S, Jones RA, Liu L, Shmookler Reis RJ, Barger SW, Mrak RE et al.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 2017-09-22
Topic: Brain proteins, microglia and lab models
Introduction Alzheimer apolipoprotein E (APOE) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to "coordinated lysosomal expression and regulation" (CLEAR) DNA motifs. Methods Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA. Results Three TFEB-regulated mRNA transcripts-SQSTM, MAP1LC3B, and LAMP2-were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites. Conclusion ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.
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APA 7th
Parcon, P. A., Balasubramaniam, M., Ayyadevara, S., Jones, R. A., Liu, L., Shmookler Reis, R. J., et al. (2018). Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1016/j.jalz.2017.07.754
Vancouver
Parcon PA, Balasubramaniam M, Ayyadevara S, Jones RA, Liu L, Shmookler Reis RJ, et al. Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2018. doi:10.1016/j.jalz.2017.07.754. PMID: 28945989.
BibTeX
@article{parcon2018-28945989,
author = {Parcon, P. A. and Balasubramaniam, M. and Ayyadevara, S. and Jones, R. A. and Liu, L. and Shmookler Reis, R. J. and Barger, S. W. and Mrak, R. E. and others},
title = {{Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2018},
doi = {10.1016/j.jalz.2017.07.754},
pmid = {28945989},
url = {https://doi.org/10.1016/j.jalz.2017.07.754}
}
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Key findings
- Results Three TFEB-regulated mRNA transcripts-SQSTM, MAP1LC3B, and LAMP2-were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains.
Why it matters
This study found that three autophagy-related gene transcripts were lower in Alzheimer's brains from APOE ε4/ε4 carriers compared to ε3/ε3 carriers, and computational modeling predicted that apoE4 binds to CLEAR DNA motifs and competes with TFEB. The findings suggest a mechanism for suppressed autophagy in APOE ε4 carriers, but no treatment is tested.
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Study details
- Evidence strengthLow
How this study scored 46/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia : the journal of the Alzheimer's Association) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2018 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 122 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 12.2 citations a year over 10 year(s) since 2018 |
| Impact for its field and year | 3 / 6 | Cited 6.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 4 other studies in this library |
| Still being cited | 2 / 4 | Cited 41 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author W. Sue T. Griffin: h-index 20 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | University of Arkansas for Medical Sciences: institution h-index 591 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28945989) |
| Free to read | 2 / 2 | Free to read |
| Total | 46 / 100 | — |
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Read the original
- DOI: 10.1016/j.jalz.2017.07.754
- PubMed: 28945989
- Original source →
- Free full text: Alzheimer s & Dementia →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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