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The HDL-Mimetic Peptide 4F Mitigates Vascular and Cortical Amyloid Pathology and Associated Neuroinflammation in a Transgenic Mouse Model of Cerebral Amyloid Angiopathy and Alzheimer's Disease
Zhong R, Chernick D, Hottman D, Tan Y, Kim M, Narayanan M, Li L.. Molecular neurobiology, 2025-03-22
Topic: Brain proteins, microglia and lab models
Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite recent advances, more effective and safer treatment options for AD are needed. Cerebral amyloid angiopathy (CAA) is one of the key pathological hallmarks of AD characterized by amyloid-β (Aβ) deposition in the cerebral vasculature and is associated with intracerebral hemorrhage, cerebrovascular dysfunction, and cognitive impairment. CAA is also considered to underlie the main adverse effect of recently FDA-approved anti-Aβ immunotherapies, namely the amyloid-related imaging abnormalities (ARIA). Substantial evidence has shown that elevated levels of high-density lipoprotein (HDL) and its main protein component, APOA-I, are associated with reduced CAA and superior cognitive function. 4F is an APOA-I/HDL-mimetic peptide and its clinical safety and activity have been demonstrated in human trials for cardiovascular diseases. The present study investigates whether treatment with 4F modulates CAA and associated cognitive deficits and neuropathologies in the well-established Tg-SwDI mouse model of CAA/AD. Age/sex-matched Tg-SwDI mice received daily treatments of 4F or vehicle (PBS), respectively, by intraperitoneal injections for 12 weeks. The results showed that 4F treatment reduced overall Aβ plaque deposition and CAA, and attenuated CAA-associated microgliosis, without significantly affecting total levels of Aβ, astrocytosis, and behavioral function. Unbiased transcriptomic analysis revealed a heightened inflammatory state in the brain of SwDI mice and that 4F treatment reversed the overactivation of vascular cells, in particular vascular smooth muscle cells, relieving cerebrovascular inflammation in CAA/AD mice. Our study provides experimental evidence for the therapeutic potential of 4F to mitigate CAA and associated pathologies in AD.
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APA 7th
Zhong, R., Chernick, D., Hottman, D., Tan, Y., Kim, M., Narayanan, M., et al. (2025). The HDL-Mimetic Peptide 4F Mitigates Vascular and Cortical Amyloid Pathology and Associated Neuroinflammation in a Transgenic Mouse Model of Cerebral Amyloid Angiopathy and Alzheimer's Disease. Molecular neurobiology. https://doi.org/10.1007/s12035-025-04859-9
Vancouver
Zhong R, Chernick D, Hottman D, Tan Y, Kim M, Narayanan M, et al. The HDL-Mimetic Peptide 4F Mitigates Vascular and Cortical Amyloid Pathology and Associated Neuroinflammation in a Transgenic Mouse Model of Cerebral Amyloid Angiopathy and Alzheimer's Disease. Molecular neurobiology. 2025. doi:10.1007/s12035-025-04859-9. PMID: 40120042.
BibTeX
@article{zhong2025-40120042,
author = {Zhong, R. and Chernick, D. and Hottman, D. and Tan, Y. and Kim, M. and Narayanan, M. and Li, L.},
title = {{The HDL-Mimetic Peptide 4F Mitigates Vascular and Cortical Amyloid Pathology and Associated Neuroinflammation in a Transgenic Mouse Model of Cerebral Amyloid Angiopathy and Alzheimer's Disease}},
journal = {Molecular neurobiology},
year = {2025},
doi = {10.1007/s12035-025-04859-9},
pmid = {40120042},
url = {https://doi.org/10.1007/s12035-025-04859-9}
}
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 7 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
- Cerebral amyloid angiopathy (CAA) is one of the key pathological hallmarks of AD characterized by amyloid-β (Aβ) deposition in the cerebral vasculature and is associated with intracerebral hemorrhage, cerebrovascular dysfunction, and cognitive impairment.
- Substantial evidence has shown that elevated levels of high-density lipoprotein (HDL) and its main protein component, APOA-I, are associated with reduced CAA and superior cognitive function. 4F is an APOA-I/HDL-mimetic peptide and its clinical safety and activity have been demonstrated in human trials for cardiovascular diseases.
- The results showed that 4F treatment reduced overall Aβ plaque deposition and CAA, and attenuated CAA-associated microgliosis, without significantly affecting total levels of Aβ, astrocytosis, and behavioral function.
- Unbiased transcriptomic analysis revealed a heightened inflammatory state in the brain of SwDI mice and that 4F treatment reversed the overactivation of vascular cells, in particular vascular smooth muscle cells, relieving cerebrovascular inflammation in CAA/AD mice.
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Study details
- Evidence strengthLow
How this study scored 41/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / 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 multicenter collaboration, so those were left out: it earned 24 of the 58 points we could judge it on, which is 41 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurobiology) |
| 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 | 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 | Laboratory or animal study (title names “transgenic”) — scores zero |
| 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 40120042) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 24 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 24 of the 58 points we could judge it on is 41 out of 100. |
| Total | 41 / 100 | — |
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