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Accumulated BCAAs and BCKAs contribute to the HFD-induced deterioration of Alzheimer's disease via a dysfunctional TREM2-related reduction in microglial β-amyloid clearance
Yang Yang, Guanjin Shi, Yanyan Ge, Shanshan Huang, Ningning Cui, Le Tan, Rui Liu, Xuefeng Yang. Journal of neuroinflammation, 2024-12-23
Topic: Gut, metabolism and diet
A high-fat diet (HFD) induces obesity and insulin resistance, which may exacerbate amyloid-β peptide (Aβ) pathology during Alzheimer's disease (AD) progression. Branched-chain amino acids (BCAAs) accumulate in obese or insulin-resistant patients and animal models. However, roles of accumulated BCAAs and their metabolites, branched-chain keto acids (BCKAs), in the HFD-induced deterioration of AD and the underlying mechanisms remains largely unclear. In this study, APPswe/PSEN1dE9 (APP/PS1) transgenic mice were fed a HFD for 6 months, and the BCAAs content of the HFD was adjusted to 200% or 50% to determine the effects of BCAAs. The HFD-fed APP/PS1 mice accumulated BCAAs and BCKAs in the serum and cortex, which was accompanied by more severe cognitive deficits and AD-related pathology. The additional or restricted intake of BCAAs aggravated or reversed these phenomena. Importantly, BCAAs and BCKAs repressed microglial phagocytosis of Aβ in vivo and in BV2 cells, which might be relevant for triggering receptor expressed on myeloid cells 2 (TREM2) dysfunction and autophagy deficiency. We found that BCAAs and BCKAs could bind to TREM2 in silico, in pure protein solutions and in the cellular environment. These molecules competed with Aβ for binding to TREM2 so that the response of TREM2 to Aβ was impaired. Moreover, BCAAs and BCKAs decreased TREM2 recycling in an mTOR-independent manner, which might also lead to TREM2 dysfunction. Our findings suggest that accumulated BCAAs and BCKAs contribute to the HFD-induced acceleration of AD progression through hypofunctional TREM2-mediated disturbances in Aβ clearance in microglia. Lowering BCAAs and BCKAs levels may become a potential dietary intervention for AD.
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APA 7th
Yang, Y., Shi, G., Ge, Y., Huang, S., Cui, N., Tan, L., et al. (2024). Accumulated BCAAs and BCKAs contribute to the HFD-induced deterioration of Alzheimer's disease via a dysfunctional TREM2-related reduction in microglial β-amyloid clearance. Journal of neuroinflammation. https://doi.org/10.1186/s12974-024-03314-1
Vancouver
Yang Y, Shi G, Ge Y, Huang S, Cui N, Tan L, et al. Accumulated BCAAs and BCKAs contribute to the HFD-induced deterioration of Alzheimer's disease via a dysfunctional TREM2-related reduction in microglial β-amyloid clearance. Journal of neuroinflammation. 2024. doi:10.1186/s12974-024-03314-1. PMID: 39716292.
BibTeX
@article{yang2024-39716292,
author = {Yang, Yang and Shi, Guanjin and Ge, Yanyan and Huang, Shanshan and Cui, Ningning and Tan, Le and Liu, Rui and Yang, Xuefeng},
title = {{Accumulated BCAAs and BCKAs contribute to the HFD-induced deterioration of Alzheimer's disease via a dysfunctional TREM2-related reduction in microglial β-amyloid clearance}},
journal = {Journal of neuroinflammation},
year = {2024},
doi = {10.1186/s12974-024-03314-1},
pmid = {39716292},
url = {https://doi.org/10.1186/s12974-024-03314-1}
}
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Key findings
- We found that BCAAs and BCKAs could bind to TREM2 in silico, in pure protein solutions and in the cellular environment.
- Our findings suggest that accumulated BCAAs and BCKAs contribute to the HFD-induced acceleration of AD progression through hypofunctional TREM2-mediated disturbances in Aβ clearance in microglia.
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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 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, multicenter collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 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 | 4 / 5 | 2024 — 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 39716292) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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