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Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer's disease neuropathology
Chen F, Swartzlander DB, Ghosh A, Fryer JD, Wang B, Zheng H.. Molecular neurodegeneration, 2021-01-31
Topic: Disease mechanisms in lab and animal studies
Background Genome-wide association studies have established clusterin (CLU) as a genetic modifier for late-onset Alzheimer's disease (AD). Both protective and risk alleles have been identified which may be associated with its expression levels. However, the physiological function of clusterin in the central nervous system remains largely unknown. Methods We examined Clu expression in mouse brains by immunohistochemistry and high-resolution imaging. We performed electrophysiological recordings and morphological analysis of dendritic spines in wild-type and Clu knockout mice. We tested synaptic function of astrocytic Clu using neuron-glia co-cultures and by AAV-mediated astroglial Clu expression in vivo. Finally, we investigated the role of astrocytic Clu on synaptic properties and amyloid pathology in 5xFAD transgenic mouse model of AD. Results We show that astrocyte secreted Clu co-localizes with presynaptic puncta of excitatory neurons. Loss of Clu led to impaired presynaptic function and reduced spine density in vivo. Neurons co-cultured with Clu-overexpressing astrocytes or treated with conditioned media from HEK293 cells transfected with Clu displayed enhanced excitatory neurotransmission. AAV-mediated astroglial Clu expression promoted excitatory neurotransmission in wild-type mice and rescued synaptic deficits in Clu knockout mice. Overexpression of Clu in the astrocytes of 5xFAD mice led to reduced Aβ pathology and fully rescued the synaptic deficits. Conclusion We identify Clu as an astrocyte-derived synaptogenic and anti-amyloid factor; the combination of these activities may influence the progression of late-onset AD.
Key findings
- Both protective and risk alleles have been identified which may be associated with its expression levels.
- Results We show that astrocyte secreted Clu co-localizes with presynaptic puncta of excitatory neurons.
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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 (Molecular neurodegeneration) |
| 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 | 2021 — 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 33517893) |
| 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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APA 7th
Chen, F., Swartzlander, D. B., Ghosh, A., Fryer, J. D., Wang, B., & Zheng, H. (2021). Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer's disease neuropathology. Molecular neurodegeneration. https://doi.org/10.1186/s13024-021-00426-7
Vancouver
Chen F, Swartzlander DB, Ghosh A, Fryer JD, Wang B, Zheng H. Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer's disease neuropathology. Molecular neurodegeneration. 2021. doi:10.1186/s13024-021-00426-7. PMID: 33517893.
BibTeX
@article{chen2021-33517893,
author = {Chen, F. and Swartzlander, D. B. and Ghosh, A. and Fryer, J. D. and Wang, B. and Zheng, H.},
title = {{Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer's disease neuropathology}},
journal = {Molecular neurodegeneration},
year = {2021},
doi = {10.1186/s13024-021-00426-7},
pmid = {33517893},
url = {https://doi.org/10.1186/s13024-021-00426-7}
}