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Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer’s Disease
Livia La Barbera, Paraskevi Krashia, Gilda Loffredo, Emma Cauzzi, Maria Luisa De Paolis, Martina Montanari, Luana Saba, Elena Spoleti et al.. Molecular Neurodegeneration, 2025-10-12
Topic: Brain proteins, microglia and lab models
The concomitant depletion of dopaminergic and serotonergic inputs within the hippocampus of C57BL/6N mice provokes a pronounced activation of microglia via the NLRP3-inflammasome pathway, accompanied by increased IL-1β expression. Pharmacological intervention with either dopaminergic (L-DOPA or A68930) or serotonergic (fluoxetine) agents abrogates this neuroinflammatory response. In the Tg2576 transgenic mouse model of amyloid pathology, which exhibits progressive Aβ deposition, superimposed midbrain degeneration markedly amplifies AD-like neuropathology. This includes exacerbation of microglial reactivity, robust astrocyte response, precocious Aβ plaque burden, and induction of pathological tau hyperphosphorylation. Notably, administration of L-DOPA or fluoxetine significantly attenuates both the astrocyte reactivity and tau hyperphosphorylation in the lesioned Tg2576 cohort. These results highlight the pivotal role of midbrain damage for the amplification of neuroinflammatory cascades and AD pathology. Moreover, they offer mechanistic insight into the faster progression to dementia in patients with midbrain deficits. By translating these findings into clinical practice, we can advance towards a precision medicine approach in disease management.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
La Barbera, L., Krashia, P., Loffredo, G., Cauzzi, E., De Paolis, M. L., Montanari, M., et al. (2025). Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer’s Disease. Molecular Neurodegeneration. https://doi.org/10.1186/s13024-025-00893-2
Vancouver
La Barbera L, Krashia P, Loffredo G, Cauzzi E, De Paolis ML, Montanari M, et al. Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer’s Disease. Molecular Neurodegeneration. 2025. doi:10.1186/s13024-025-00893-2. PMID: 41077614.
BibTeX
@article{labarbera2025-41077614,
author = {La Barbera, Livia and Krashia, Paraskevi and Loffredo, Gilda and Cauzzi, Emma and De Paolis, Maria Luisa and Montanari, Martina and Saba, Luana and Spoleti, Elena and others},
title = {{Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer’s Disease}},
journal = {Molecular Neurodegeneration},
year = {2025},
doi = {10.1186/s13024-025-00893-2},
pmid = {41077614},
url = {https://doi.org/10.1186/s13024-025-00893-2}
}
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
- The concomitant depletion of dopaminergic and serotonergic inputs within the hippocampus of C57BL/6N mice provokes a pronounced activation of microglia via the NLRP3-inflammasome pathway, accompanied by increased IL-1β expression.
- Pharmacological intervention with either dopaminergic (L-DOPA or A68930) or serotonergic (fluoxetine) agents abrogates this neuroinflammatory response.
- In the Tg2576 transgenic mouse model of amyloid pathology, which exhibits progressive Aβ deposition, superimposed midbrain degeneration markedly amplifies AD-like neuropathology.
- This includes exacerbation of microglial reactivity, robust astrocyte response, precocious Aβ plaque burden, and induction of pathological tau hyperphosphorylation.
- Notably, administration of L-DOPA or fluoxetine significantly attenuates both the astrocyte reactivity and tau hyperphosphorylation in the lesioned Tg2576 cohort.
Why it matters
In mice, damage to midbrain dopamine and serotonin inputs triggered microglial activation and worsened amyloid and tau pathology, while L-DOPA or fluoxetine reduced astrocyte reactivity and tau hyperphosphorylation. These findings are from animal experiments and suggest a possible link to faster dementia progression in people with midbrain deficits, but they do not show a treatment for patients.
Study details
- Evidence strengthModerate
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 randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular Neurodegeneration) |
| Journal's citation record | 2 / 4 | Molecular Neurodegeneration: journal h-index 164 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” 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 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 13 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 7.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 13 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Marcello D’Amelio: h-index 48 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Pisa: institution h-index 907 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41077614) |
| Free to read | 2 / 2 | Free to read |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/s13024-025-00893-2
- PubMed: 41077614
- Original source →
- Free full text: Molecular Neurodegeneration →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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