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PDE2A Modulation Attenuates Aβ-Induced Neuronal Injury and Associated Oxidative, Inflammatory, and Apoptotic Responses
Li H, Cheng Y, Lin X, Feng Y, Du B, Dou B, Sheng Z, Xu F et al.. Research Square, 2026-10-01
Topic: Inflammation, microglia and astrocytes
Background Alzheimer’s disease (AD) involves progressive neuronal injury driven in part by Aβ-associated oxidative stress, inflammatory activation, and apoptotic signaling. Cyclic nucleotide dysregulation has emerged as a contributing factor in these processes. This study evaluated the neuroprotective effects of BML-288, a phosphodiesterase-2A (PDE2A) inhibitor, in Aβ-induced injury models. Methods HT-22 neuronal cells were exposed to Aβ₁–₄₂ with or without BML-288 co-treatment. A hippocampal CA1 Aβ microinjection mouse model was used to assess in vivo effects. Oxidative stress markers, inflammatory cytokines, apoptosis-related proteins, and cAMP/cGMP levels were measured using biochemical assays and Western blotting. PDE2A overexpression and knockdown were used to further examine the involvement of PDE2A in Aβ-induced cellular responses. Cognitive performance was evaluated using the Morris water maze, Y-maze, and novel object recognition tests. Results Aβ exposure increased PDE2A expression and reduced intracellular cAMP and cGMP levels in HT-22 cells, whereas BML-288 partially reversed these changes. BML-288 also reduced Aβ-related increases in ROS and MDA, restored SOD activity, and decreased IL-1β and TNF-α levels in both cell cultures and hippocampal tissue. Bax and total Caspase-3 expression were increased after Aβ exposure and attenuated by BML-288, accompanied by modulation of Bcl-2 expression. PDE2A overexpression enhanced oxidative and inflammatory responses, whereas PDE2A knockdown attenuated Aβ-associated cellular stress. In vivo, BML-288 improved performance across spatial learning and memory tasks. Conclusions Across cellular and animal Aβ injury models, BML-288 attenuated oxidative and inflammatory disturbances, modulated apoptosis-related protein expression, and improved cognitive outcomes. These findings suggest that PDE2A inhibition may help counteract cyclic nucleotide dysregulation associated with Aβ-induced neuronal stress and support further investigation of PDE2A-related signaling and BML-288 in Aβ-associated neurotoxicity.
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APA 7th
Li, H., Cheng, Y., Lin, X., Feng, Y., Du, B., Dou, B., et al. (2026). PDE2A Modulation Attenuates Aβ-Induced Neuronal Injury and Associated Oxidative, Inflammatory, and Apoptotic Responses. Research Square. https://doi.org/10.21203/rs.3.rs-10975363/v1
Vancouver
Li H, Cheng Y, Lin X, Feng Y, Du B, Dou B, et al. PDE2A Modulation Attenuates Aβ-Induced Neuronal Injury and Associated Oxidative, Inflammatory, and Apoptotic Responses. Research Square. 2026. doi:10.21203/rs.3.rs-10975363/v1.
BibTeX
@article{li2026-66649645,
author = {Li, H. and Cheng, Y. and Lin, X. and Feng, Y. and Du, B. and Dou, B. and Sheng, Z. and Xu, F. and others},
title = {{PDE2A Modulation Attenuates Aβ-Induced Neuronal Injury and Associated Oxidative, Inflammatory, and Apoptotic Responses}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10975363/v1},
url = {https://doi.org/10.21203/rs.3.rs-10975363/v1}
}
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Key findings
- Results Aβ exposure increased PDE2A expression and reduced intracellular cAMP and cGMP levels in HT-22 cells, whereas BML-288 partially reversed these changes.
- These findings suggest that PDE2A inhibition may help counteract cyclic nucleotide dysregulation associated with Aβ-induced neuronal stress and support further investigation of PDE2A-related signaling and BML-288 in Aβ-associated neurotoxicity.
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, studied in people 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 (Research Square) |
| 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 | 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 | 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. |
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