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The contribution of activated astrocytes to Aβ production: implications for Alzheimer's disease pathogenesis
Zhao J, O'Connor T, Vassar R.. Journal of neuroinflammation, 2011-11-02
Topic: Amyloid, tau and blood-test diagnosis
Background β-Amyloid (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis. Neurons are major sources of Aβ in the brain. However, astrocytes outnumber neurons by at least five-fold. Thus, even a small level of astrocytic Aβ production could make a significant contribution to Aβ burden in AD. Moreover, activated astrocytes may increase Aβ generation. β-Site APP cleaving enzyme 1 (BACE1) cleavage of amyloid precursor protein (APP) initiates Aβ production. Here, we explored whether pro-inflammatory cytokines or Aβ42 would increase astrocytic levels of BACE1, APP, and β-secretase processing, implying a feed-forward mechanism of astrocytic Aβ production. Methods Mouse primary astrocytes were treated with combinations of LPS, TNF-α, IFN-γ, and IL-1β and analyzed by immunoblot and ELISA for endogenous BACE1, APP, and secreted Aβ40 levels. Inhibition of JAK and iNOS signaling in TNF-α+IFN-γ-stimulated astrocytes was also analyzed. In addition, C57BL/6J or Tg2576 mouse astrocytes were treated with oligomeric or fibrillar Aβ42 and analyzed by immunoblot for levels of BACE1, APP, and APPsβsw. Astrocytic BACE1 and APP mRNA levels were measured by TaqMan RT-PCR. Results TNF-α+IFN-γ stimulation significantly increased levels of astrocytic BACE1, APP, and secreted Aβ40. BACE1 and APP elevations were post-transcriptional at early time-points, but became transcriptional with longer TNF-α+IFN-γ treatment. Despite a ~4-fold increase in astrocytic BACE1 protein level following TNF-α+IFN-γ stimulation, BACE1 mRNA level was significantly decreased suggesting a post-transcriptional mechanism. Inhibition of iNOS and JAK did not reduce TNF-α+IFN-γ-stimulated elevation of astrocytic BACE1, APP, and Aβ40, except that JAK inhibition blocked the APP increase. Finally, oligomeric and fibrillar Aβ42 dramatically increased levels of astrocytic BACE1, APP, and APPsβsw through transcriptional mechanisms, at least in part. Conclusions Cytokines including TNF-α+IFN-γ increase levels of endogenous BACE1, APP, and Aβ and stimulate amyloidogenic APP processing in astrocytes. Oligomeric and fibrillar Aβ42 also increase levels of astrocytic BACE1, APP, and β-secretase processing. Together, our results suggest a cytokine- and Aβ42-driven feed-forward mechanism that promotes astrocytic Aβ production. Given that astrocytes greatly outnumber neurons, activated astrocytes may represent significant sources of Aβ during neuroinflammation in AD.
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APA 7th
Zhao, J., O'Connor, T., & Vassar, R. (2011). The contribution of activated astrocytes to Aβ production: implications for Alzheimer's disease pathogenesis. Journal of neuroinflammation. https://doi.org/10.1186/1742-2094-8-150
Vancouver
Zhao J, O'Connor T, Vassar R. The contribution of activated astrocytes to Aβ production: implications for Alzheimer's disease pathogenesis. Journal of neuroinflammation. 2011. doi:10.1186/1742-2094-8-150. PMID: 22047170.
BibTeX
@article{zhao2011-22047170,
author = {Zhao, J. and O'Connor, T. and Vassar, R.},
title = {{The contribution of activated astrocytes to Aβ production: implications for Alzheimer's disease pathogenesis}},
journal = {Journal of neuroinflammation},
year = {2011},
doi = {10.1186/1742-2094-8-150},
pmid = {22047170},
url = {https://doi.org/10.1186/1742-2094-8-150}
}
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Key findings
- Thus, even a small level of astrocytic Aβ production could make a significant contribution to Aβ burden in AD.
- Results TNF-α+IFN-γ stimulation significantly increased levels of astrocytic BACE1, APP, and secreted Aβ40.
- Despite a ~4-fold increase in astrocytic BACE1 protein level following TNF-α+IFN-γ stimulation, BACE1 mRNA level was significantly decreased suggesting a post-transcriptional mechanism.
- Together, our results suggest a cytokine- and Aβ42-driven feed-forward mechanism that promotes astrocytic Aβ production.
- Given that astrocytes greatly outnumber neurons, activated astrocytes may represent significant sources of Aβ during neuroinflammation in AD.
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Study details
- Evidence strengthLow
How this study scored 40/100
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 and multi-centre collaboration, so those were left out: it earned 23 of the 58 points we could judge it on, which is 40 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of neuroinflammation) |
| 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 | 1 / 5 | 2011 — within 20 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 22047170) |
| Free to read | 2 / 2 | Free to read |
| Points | 23 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 23 of the 58 points we could judge it on is 40 out of 100. |
| Total | 40 / 100 | — |
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