Islet amyloid polypeptide exacerbates cognitive impairment, neuroinflammation, and hippocampal Aβ plaque deposition in Alzheimer’s disease mice by inhibiting the PI3K/Akt pathway

@article{xiangqian2026islet,
  title = {{Islet amyloid polypeptide exacerbates cognitive impairment, neuroinflammation, and hippocampal Aβ plaque deposition in Alzheimer’s disease mice by inhibiting the PI3K/Akt pathway}},
  author = {Feng Xiangqian and Zhou Huadong},
  journal = {陆军军医大学学报},
  year = {2026},
  month = oct,
  doi = {10.16016/j.2097-0927.202606040},
  url = {https://doi.org/10.16016/j.2097-0927.202606040},
  note = {CC BY},
}

TY  - JOUR
TI  - Islet amyloid polypeptide exacerbates cognitive impairment, neuroinflammation, and hippocampal Aβ plaque deposition in Alzheimer’s disease mice by inhibiting the PI3K/Akt pathway
AU  - Feng Xiangqian
AU  - Zhou Huadong
PY  - 2026
DA  - 2026/10/30
JO  - 陆军军医大学学报
DO  - 10.16016/j.2097-0927.202606040
UR  - https://doi.org/10.16016/j.2097-0927.202606040
AB  - Objective Islet amyloid polypeptide (IAPP) is an active peptide synthesized and secreted by pancreatic β-cells, which forms amyloid plaques in the islets under diabetic conditions. This study aims to determine the effect of IAPP on cognitive impairment, neuroinflammatory response, and other pathological injuries in Alzheimer’s disease (AD) mice. Methods Six-month-old female C57BL/6J wild-type (WT) and APP/PS1 transgenic AD mice, with an initial body weight of 20 to 23 g, were randomly divided into 4 groups (n=5): WT group (intraperitoneal injection of equal volume of PBS), WT+IAPP group (intraperitoneal injection of 200 μg/kg IAPP), AD group (intraperitoneal injection of equal volume of PBS), and AD+IAPP group (intraperitoneal injection of 200 μg/kg IAPP). Intraperitoneal injection of IAPP was given to the corresponding mice for 10 consecutive weeks. Morris water maze test was performed to evaluate cognitive function. Immunohistochemistry was applied to detect the number and area of Aβ plaques in the hippocampus. Transmission electron microscopy (TEM) was used to observe the ultrastructural changes in hippocampal neurons. Biochemical kits were employed to detect the levels of hydrogen peroxide (H2O2) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the hippocampal tissues. ELISA was utilized to measure the levels of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α, as well as serum amyloid β-protein 42 (Aβ42) concentration. Microarray analysis was conducted to screen differentially expressed mRNAs, followed by GO and KEGG enrichment analyses. RT-qPCR was performed to measure the expression of differential mRNAs. Western blotting was carried out to detect the relative expression levels of proteins related to the PI3K/Akt signaling pathway in hippocampal tissues. Results Morris water maze test demonstrated that the learning and memory abilities were no statistical difference between the WT+IAPP group and the WT group, significantly decreased in the AD group than the WT group(P<0.05), and obviously decreased in the AD+IAPP group than the AD group (P<0.05). Immunohistochemical staining revealed that compared with the WT group, the number and area of hippocampal Aβ plaques in the WT+IAPP group showed no significant difference, while those in the AD group were significantly increased(P<0.01); compared with the AD group, the number and area of Aβ plaques in the AD+IAPP group were significantly increased (P<0.01). TEM demonstrated aggravated mitochondrial damage and a remarkable reduction in synaptic number in hippocampal neurons of the AD+IAPP group compared with the AD group (P<0.05). The level of H₂O₂ in the hippocampus was significantly increased, while the activities of SOD and GSH-Px were significantly decreased in the AD+IAPP group compared with the AD group (P<0.05). The hippocampal levels of IL-1β, IL-6 and TNF-α were significantly elevated, whereas serum Aβ42 concentration was notably reduced in the AD+IAPP group compared with the AD group (P<0.05). A total of 555 differentially expressed mRNAs (236 upregulated and 319 downregulated) were screened out by microarray, and RT-qPCR verification results were consistent with the results of microarray. GO enrichment analysis indicated that these differentially expressed genes were involved in transmembrane signal transduction and neural development. KEGG analysis revealed that the differential genes were enriched in the PI3K/Akt signaling pathway. Western blotting showed that the protein expression levels of PI3K, Akt, p-PI3K, and p-Akt in hippocampal neurons were significantly decreased in the AD+IAPP group compared with the AD group (P<0.05). Conclusion IAPP can aggravate cognitive dysfunction, enhance inflammatory responses, and promote hippocampal Aβ-plaque deposition in AD mice. Its underlying mechanism may be related to the inhibition of PI3K/Akt signaling-pathway activity.
SN  - 2097-0927
ER  -