Home › Research › Disease mechanisms
Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice
Aceituno K, Granger K, Leon J, Godoy-Lugo JA, Young KE, Joseph T, Liu K, Kruijff I et al.. bioRxiv, 2026-09-24
Topic: Gut, metabolism and diet
Physical exercise promotes systemic and neural adaptations that support healthy brain aging and may mitigate Alzheimer’s disease (AD) progression. However, the capacity of the AD-afflicted brain to mount and translate exercise-responsive molecular adaptations into neuroprotection remains unclear. Here, we examined the effects of long-term voluntary wheel running (VWR) on molecular, neuropathological, and behavioral outcomes in independently studied male and female 5xFAD mice. VWR elicited expected metabolic and transcriptional remodeling of inguinal white adipose tissue, confirming engagement of exercise-responsive peripheral biology. In contrast, hippocampal transcriptional responses were modest, with few differentially expressed genes and coordinated changes emerging primarily at the pathway level. These responses involved synaptic, neuroimmune, mitochondrial, neurotrophic, and monoaminergic processes and differed qualitatively between the two groups. Several components of the canonical hippocampal exercise response also failed to converge into coordinated cellular adaptations: synaptic protein abundance changed without altering synapse density, while neurotrophic, neurogenic, and vascular responses showed little correspondence across molecular and cellular measures. VWR also produced little change in hippocampal amyloid pathology or behavioral function despite sustained exercise engagement. Together, these findings demonstrate that the 5xFAD brain retains modest molecular responsiveness to prolonged voluntary exercise but may be unable to mount a sufficiently robust or coordinated response to produce broad neuroprotective effects. These findings highlight disease context as an important determinant of the efficacy of exercise-based interventions in neurodegenerative disease.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Aceituno, K., Granger, K., Leon, J., Godoy-Lugo, J. A., Young, K. E., Joseph, T., et al. (2026). Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice. bioRxiv. https://doi.org/10.64898/2026.09.16.752181
Vancouver
Aceituno K, Granger K, Leon J, Godoy-Lugo JA, Young KE, Joseph T, et al. Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice. bioRxiv. 2026. doi:10.64898/2026.09.16.752181.
BibTeX
@article{aceituno2026-d385a25d,
author = {Aceituno, K. and Granger, K. and Leon, J. and Godoy-Lugo, J. A. and Young, K. E. and Joseph, T. and Liu, K. and Kruijff, I. and others},
title = {{Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.16.752181},
url = {https://doi.org/10.64898/2026.09.16.752181}
}
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- Together, these findings demonstrate that the 5xFAD brain retains modest molecular responsiveness to prolonged voluntary exercise but may be unable to mount a sufficiently robust or coordinated response to produce broad neuroprotective effects.
- These findings highlight disease context as an important determinant of the efficacy of exercise-based interventions in neurodegenerative disease.
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 →
Read the original
Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.
Related studies in Disease mechanisms
Also tagged “exercise-training”
125 studies in the library carry the topic tag “exercise-training”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 125 tagged studies.