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Insulin fails to mitigate amyloid pathology but modulates intestinal morphology in the 5xFAD model revealed by synchrotron-based XPCT
Ayan E, Palermo F, Cavioli G, Bostan S, Dogan BZ, Kilic K, Kaplan AA, Bukreeva I et al.. bioRxiv, 2026-10-16
Topic: Gut, metabolism and diet
Intranasal insulin has been investigated as a metabolic intervention in Alzheimer’s disease (AD), but its effects across the brain–gut axis remain unclear. We combined multiscale synchrotron X-ray phase-contrast tomography (XPCT), amyloid-β immunofluorescence, and fecal metaproteomics to examine structural and molecular responses in 5xFAD mice. Twenty-four mice representing wild-type and 5xFAD genotypes, saline and insulin conditions, and terminal ages of 2 and 6 months received insulin at 1 U/mouse/day for 5 weeks. Micro-XPCT visualized plaque-like deposits, nanoXPCT revealed their heterogeneous internal organization, and MOAB-2 labeling provided qualitative support for amyloid pathology. Detectable plaque burden was not lower after treatment: deposits occurred in two of three treated versus none of three untreated 5xFAD mice at 2 months, and treated animals had higher descriptive regional means at 6 months. In the ileum, insulin was associated with lower villus length and crypt depth in 6-month-old 5xFAD mice, whereas no significant differences were detected at 2 months. Fecal profiles retained broad taxonomic overlap but differed in functional annotations, with hydrolase-associated fractions of 81%, 92%, 96%, and 93% across untreated wild-type, treated wild-type, untreated 5xFAD, and treated 5xFAD conditions, respectively, within the selected peptide subset. Thus, lower ileal dimensions coexisted with non-reduced detectable brain plaque burden and a fecal protein profile distinct from untreated wild type. Together, these findings reveal contrasting central and peripheral patterns following intranasal insulin treatment in 5xFAD mice: no detectable reduction in cerebral plaque burden, alongside attenuation of selected ileal structural alterations and distinct fecal metaproteomic profiles. Although exploratory, the findings raise the possibility that intranasal insulin alters amyloid compartmentalization or plaque detectability rather than promoting amyloid clearance, while producing distinct peripheral remodeling.
Key findings
- Micro-XPCT visualized plaque-like deposits, nanoXPCT revealed their heterogeneous internal organization, and MOAB-2 labeling provided qualitative support for amyloid pathology.
- Detectable plaque burden was not lower after treatment: deposits occurred in two of three treated versus none of three untreated 5xFAD mice at 2 months, and treated animals had higher descriptive regional means at 6 months.
- In the ileum, insulin was associated with lower villus length and crypt depth in 6-month-old 5xFAD mice, whereas no significant differences were detected at 2 months.
- Together, these findings reveal contrasting central and peripheral patterns following intranasal insulin treatment in 5xFAD mice: no detectable reduction in cerebral plaque burden, alongside attenuation of selected ileal structural alterations and distinct fecal metaproteomic profiles.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 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 and randomised / 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 and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| 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 | 5 / 5 | 2026 — within 1 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 “5xfad”) — scores zero |
| 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Ayan, E., Palermo, F., Cavioli, G., Bostan, S., Dogan, B. Z., Kilic, K., et al. (2026). Insulin fails to mitigate amyloid pathology but modulates intestinal morphology in the 5xFAD model revealed by synchrotron-based XPCT. bioRxiv. https://doi.org/10.64898/2026.10.10.758244
Vancouver
Ayan E, Palermo F, Cavioli G, Bostan S, Dogan BZ, Kilic K, et al. Insulin fails to mitigate amyloid pathology but modulates intestinal morphology in the 5xFAD model revealed by synchrotron-based XPCT. bioRxiv. 2026. doi:10.64898/2026.10.10.758244.
BibTeX
@article{ayan2026-b4d44c1a,
author = {Ayan, E. and Palermo, F. and Cavioli, G. and Bostan, S. and Dogan, B. Z. and Kilic, K. and Kaplan, A. A. and Bukreeva, I. and others},
title = {{Insulin fails to mitigate amyloid pathology but modulates intestinal morphology in the 5xFAD model revealed by synchrotron-based XPCT}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.10.758244},
url = {https://doi.org/10.64898/2026.10.10.758244}
}
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