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PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and Neuroinflammation
Mengqi Zhang, Anudari Letian, Gregory A Mohl, Brynn Kroke, Kajsa Arkelius, Claire D Clelland, Emily L Goldberg, Neel S Singhal. bioRxiv : the preprint server for biology, 2025-10-31
Topic: Inflammation, microglia and astrocytes
Cerebral small vessel disease (CSVD) is strongly linked to metabolic risk factors and represents a major cause of vascular cognitive impairment and dementia. The interactions of genetic and environmental risk factors driving cerebrovascular pathology in metabolic syndrome are poorly understood. Here, we characterize neuroinflammatory and neurodegenerative phenotypes in a mouse model of metabolic syndrome with atherosclerosis induced by hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) overexpression combined with high-fat diet (HFD). PCSK9+HFD mice exhibit hallmark features of CSVD including vascular rarefaction, impaired neurovascular coupling, blood-brain barrier disruption, white matter injury, neuronal loss, and cognitive deficits. Notably, we identify lipid-droplet accumulating microglia (LDAM) as a distinct cellular phenotype that emerges in response to metabolic stress and correlates with cerebrovascular dysfunction. Three-dimensional light sheet microscopy reveals widespread vascular network disruption. Immunophenotyping demonstrates that microglia in PCSK9+HFD group exhibit enhanced phagocytic activation and ramification complexity yet accumulate perivascular amyloid-β, suggesting impaired clearance capacity. Importantly, we observed vascular amyloid-β deposition in wild-type mice without genetic Alzheimer's disease mutations, suggesting that metabolic stress contributes to cerebrovascular amyloid pathology. PCSK9+HFD mice displayed recognition memory deficits and increased anxiety-like behavior. Our findings establish that severe hypercholesterolemia accelerates CSVD pathogenesis, and identify LDAM as a distinct pathological feature linking systemic metabolic syndrome to cerebrovascular dysfunction and cognitive impairment.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Zhang, M., Letian, A., Mohl, G. A., Kroke, B., Arkelius, K., Clelland, C. D., et al. (2025). PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and Neuroinflammation. bioRxiv : the preprint server for biology. https://doi.org/10.1101/2025.10.29.685380
Vancouver
Zhang M, Letian A, Mohl GA, Kroke B, Arkelius K, Clelland CD, et al. PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and Neuroinflammation. bioRxiv : the preprint server for biology. 2025. doi:10.1101/2025.10.29.685380. PMID: 41278621.
BibTeX
@article{zhang2025-41278621,
author = {Zhang, Mengqi and Letian, Anudari and Mohl, Gregory A and Kroke, Brynn and Arkelius, Kajsa and Clelland, Claire D and Goldberg, Emily L and Singhal, Neel S},
title = {{PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and Neuroinflammation}},
journal = {bioRxiv : the preprint server for biology},
year = {2025},
doi = {10.1101/2025.10.29.685380},
pmid = {41278621},
url = {https://doi.org/10.1101/2025.10.29.685380}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- Importantly, we observed vascular amyloid-β deposition in wild-type mice without genetic Alzheimer's disease mutations, suggesting that metabolic stress contributes to cerebrovascular amyloid pathology.
- Our findings establish that severe hypercholesterolemia accelerates CSVD pathogenesis, and identify LDAM as a distinct pathological feature linking systemic metabolic syndrome to cerebrovascular dysfunction and cognitive impairment.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 22 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on 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, multicenter collaboration and free to read, so those were left out: it earned 13 of the 60 points we could judge it on, which is 22 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv : the preprint server for biology) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 4 / 5 | 2025 — within 3 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) |
| Randomized / blinded | 0 / 2 | No randomization 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 |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41278621) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 13 / 60 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 13 of the 60 points we could judge it on is 22 out of 100. |
| Total | 22 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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