Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer's disease
Charis Ringland, Jonas Elias Schweig, Daniel Paris, Ben Shackleton, Cillian E Lynch, Maxwell Eisenbaum, Michael Mullan, Fiona Crawford et al.. Neurobiology of aging, 2020-07-03
Topic: Inflammation, microglia and astrocytes
Apolipoprotein E (APOE) has been shown to influence amyloid-β (Aβ) clearance from the brain in an isoform-specific manner. Our prior work showed that Aβ transit across the blood-brain-barrier was reduced by apoE4, compared to other apoE isoforms, due to elevated lipoprotein receptor shedding in brain endothelia. Recently, we demonstrated that matrix metallopeptidase 9 (MMP-9) induces lipoprotein receptor proteolysis in an apoE isoform-dependent manner, which impacts Aβ elimination from the brain. The current studies interrogated the relationship between apoE and MMP-9 and found that apoE impacted proMMP-9 cellular secretion from brain endothelia (apoE2 < apoE3 = apoE4). In a cell-free assay, apoE dose-dependently reduced MMP-9 activity, with apoE4 showing a significantly weaker ability to inhibit MMP-9 function than apoE2 or apoE3. Finally, we observed elevated MMP-9 expression and activity in the cerebrovasculature of both human and animal AD brain specimens with an APOE4 genotype. Collectively, these findings suggest a role for apoE in regulating MMP-9 disposition and may describe the effect of apoE4 on Aβ pathology in the AD brain.
Key findings
- Our prior work showed that Aβ transit across the blood-brain-barrier was reduced by apoE4, compared to other apoE isoforms, due to elevated lipoprotein receptor shedding in brain endothelia.
- Recently, we demonstrated that matrix metallopeptidase 9 (MMP-9) induces lipoprotein receptor proteolysis in an apoE isoform-dependent manner, which impacts Aβ elimination from the brain.
- In a cell-free assay, apoE dose-dependently reduced MMP-9 activity, with apoE4 showing a significantly weaker ability to inhibit MMP-9 function than apoE2 or apoE3.
- Finally, we observed elevated MMP-9 expression and activity in the cerebrovasculature of both human and animal AD brain specimens with an APOE4 genotype.
- Collectively, these findings suggest a role for apoE in regulating MMP-9 disposition and may describe the effect of apoE4 on Aβ pathology in the AD brain.
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Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people 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, multi-centre collaboration and free to read, so those were left out: it earned 22 of the 56 points we could judge it on, which is 39 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurobiology of aging) |
| 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 | 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 | 2020 — 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 | — / 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 32758917) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 22 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 22 of the 56 points we could judge it on is 39 out of 100. |
| Total | 39 / 100 | — |
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APA 7th
Ringland, C., Schweig, J. E., Paris, D., Shackleton, B., Lynch, C. E., Eisenbaum, M., et al. (2020). Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer's disease. Neurobiology of aging. https://doi.org/10.1016/j.neurobiolaging.2020.06.018
Vancouver
Ringland C, Schweig JE, Paris D, Shackleton B, Lynch CE, Eisenbaum M, et al. Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer's disease. Neurobiology of aging. 2020. doi:10.1016/j.neurobiolaging.2020.06.018. PMID: 32758917.
BibTeX
@article{ringland2020-32758917,
author = {Ringland, Charis and Schweig, Jonas Elias and Paris, Daniel and Shackleton, Ben and Lynch, Cillian E and Eisenbaum, Maxwell and Mullan, Michael and Crawford, Fiona and others},
title = {{Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer's disease}},
journal = {Neurobiology of aging},
year = {2020},
doi = {10.1016/j.neurobiolaging.2020.06.018},
pmid = {32758917},
url = {https://doi.org/10.1016/j.neurobiolaging.2020.06.018}
}