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Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer's disease neuropathology
Arnsten AFT, Perone I, Wang M, Yang S, Uchendu S, Bolat D, Datta D.. Frontiers in aging neuroscience, 2025-07-15
Topic: Brain proteins, microglia and lab models
The common, late onset form of Alzheimer's disease (AD) selectively impacts higher brain circuits, with tau pathology and neurodegeneration preferentially afflicting glutamatergic neurons in the limbic and association cortices. Understanding this selective vulnerability may help reveal the etiology of sporadic AD and therapeutic targets for prevention. The current review describes that these vulnerable circuits express magnified calcium signaling needed for higher cognition and memory, but that heightened calcium signaling becomes toxic when dysregulated by age and inflammation. Many of the earliest pathological events in AD are challenging to study in human brain, as proteins such as tau rapidly dephosphorylate postmortem. However, they can be studied in aging macaques, who are all APOE-ε4 homozygotes and naturally develop cognitive deficits, calcium dysregulation, synapse loss, tau and amyloid pathology and autophagic degeneration, including elevated plasma pT217Tau, a new blood biomarker of incipient AD. High resolution nanoscale imaging of aging macaque brains reveals the earliest stages of soluble tau pathology and its relationships with Aβ 42 and calcium signaling. These data indicate that inflammation erodes regulation of calcium signaling leading to the activation of calpain-2, which drives tau hyperphosphorylation, APP cleavage to Aβ 42 and autophagic degeneration. These in turn propel further calcium dysregulation to drive vicious cycles. Restoring calcium dysregulation, e.g., with calpain-2 inhibitors, thus may be a rational strategy for slowing or preventing AD pathology. Recent data show that an agent that reduces GCPII inflammation and restores mGluR3 regulation of calcium reduced tau pathology in aged macaques, encouraging this approach. Targeting inflammation and dysregulated calcium may be especially helpful for patients who are APOE-ε4 carriers and insufficiently aided by current anti-amyloid antibody treatments.
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APA 7th
Arnsten, A. F. T., Perone, I., Wang, M., Yang, S., Uchendu, S., Bolat, D., et al. (2025). Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer's disease neuropathology. Frontiers in aging neuroscience. https://doi.org/10.3389/fnagi.2025.1610350
Vancouver
Arnsten AFT, Perone I, Wang M, Yang S, Uchendu S, Bolat D, et al. Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer's disease neuropathology. Frontiers in aging neuroscience. 2025. doi:10.3389/fnagi.2025.1610350. PMID: 40735190.
BibTeX
@article{arnsten2025-40735190,
author = {Arnsten, A. F. T. and Perone, I. and Wang, M. and Yang, S. and Uchendu, S. and Bolat, D. and Datta, D.},
title = {{Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer's disease neuropathology}},
journal = {Frontiers in aging neuroscience},
year = {2025},
doi = {10.3389/fnagi.2025.1610350},
pmid = {40735190},
url = {https://doi.org/10.3389/fnagi.2025.1610350}
}
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Key findings
- These data indicate that inflammation erodes regulation of calcium signaling leading to the activation of calpain-2, which drives tau hyperphosphorylation, APP cleavage to Aβ 42 and autophagic degeneration.
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Study details
- Evidence strengthLow
How this study scored 45/100
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. 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 multi-centre collaboration, so those were left out: it earned 26 of the 58 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Frontiers in aging neuroscience) |
| 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 | 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 | — / 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 | 2 / 2 | Indexed in PubMed (PMID 40735190) |
| Free to read | 2 / 2 | Free to read |
| Points | 26 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 26 of the 58 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
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