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Bromo-protopine, a novel protopine derivative, alleviates tau pathology by activating chaperone-mediated autophagy for Alzheimer's disease therapy
Sreenivasmurthy SG, Iyaswamy A, Krishnamoorthi S, Reddi RN, Kammala AK, Vasudevan K, Senapati S, Zhu Z et al.. Frontiers in molecular biosciences, 2022-10-26
Topic: Brain proteins, microglia and lab models
Emerging evidence from Alzheimer's disease (AD) patients suggests that reducing tau pathology can restore cognitive and memory loss. To reduce tau pathology, it is critical to find brain-permeable tau-degrading small molecules that are safe and effective. HDAC6 inhibition has long been considered a safe and effective therapy for tau pathology. Recently, we identified protopine as a dibenzazecine alkaloid with anti-HDAC6 and anti-AD activities. In this study, we synthesized and tested novel protopine derivatives for their pharmacological action against AD. Among them, bromo-protopine (PRO-Br) demonstrated a two-fold increase in anti-HDAC6 activity and improved anti-tau activities compared to the parent compound in both in vitro and in vivo AD models. Furthermore, molecular docking results showed that PRO-Br binds to HDAC6, with a ∆G value of -8.4 kcal/mol and an IC 50 value of 1.51 µM. In neuronal cell lines, PRO-Br reduced pathological tau by inducing chaperone-mediated autophagy (CMA). In 3xTg-AD and P301S tau mice models, PRO-Br specifically decreased the pathogenic hyperphosphorylated tau clumps and led to the restoration of memory functions. In addition, PRO-Br treatment promoted the clearance of pathogenic tau by enhancing the expression of molecular chaperones (HSC70) and lysosomal markers (LAMP2A) via CMA in AD models. Our data strongly suggest that administration of the brain-permeable protopine derivative PRO-Br, could be a viable anti-tau therapeutic strategy for AD.
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APA 7th
Sreenivasmurthy, S. G., Iyaswamy, A., Krishnamoorthi, S., Reddi, R. N., Kammala, A. K., Vasudevan, K., et al. (2022). Bromo-protopine, a novel protopine derivative, alleviates tau pathology by activating chaperone-mediated autophagy for Alzheimer's disease therapy. Frontiers in molecular biosciences. https://doi.org/10.3389/fmolb.2022.1030534
Vancouver
Sreenivasmurthy SG, Iyaswamy A, Krishnamoorthi S, Reddi RN, Kammala AK, Vasudevan K, et al. Bromo-protopine, a novel protopine derivative, alleviates tau pathology by activating chaperone-mediated autophagy for Alzheimer's disease therapy. Frontiers in molecular biosciences. 2022. doi:10.3389/fmolb.2022.1030534. PMID: 36387280.
BibTeX
@article{sreenivasmurthy2022-36387280,
author = {Sreenivasmurthy, S. G. and Iyaswamy, A. and Krishnamoorthi, S. and Reddi, R. N. and Kammala, A. K. and Vasudevan, K. and Senapati, S. and Zhu, Z. and others},
title = {{Bromo-protopine, a novel protopine derivative, alleviates tau pathology by activating chaperone-mediated autophagy for Alzheimer's disease therapy}},
journal = {Frontiers in molecular biosciences},
year = {2022},
doi = {10.3389/fmolb.2022.1030534},
pmid = {36387280},
url = {https://doi.org/10.3389/fmolb.2022.1030534}
}
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Key findings
- Emerging evidence from Alzheimer's disease (AD) patients suggests that reducing tau pathology can restore cognitive and memory loss.
- Among them, bromo-protopine (PRO-Br) demonstrated a two-fold increase in anti-HDAC6 activity and improved anti-tau activities compared to the parent compound in both in vitro and in vivo AD models.
- Furthermore, molecular docking results showed that PRO-Br binds to HDAC6, with a ∆G value of -8.4 kcal/mol and an IC 50 value of 1.51 µM.
- Our data strongly suggest that administration of the brain-permeable protopine derivative PRO-Br, could be a viable anti-tau therapeutic strategy for AD.
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Study details
- Evidence strengthLow
How this study scored 43/100
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 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Frontiers in molecular biosciences) |
| 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 | 3 / 5 | 2022 — within 6 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 36387280) |
| Free to read | 2 / 2 | Free to read |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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