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Circular RNAs (circRNAs) are a subclass of non-coding RNAs which have demonstrated potential as biomarkers for Alzheimer's disease (AD). In this study, we conducted a comprehensive exploration of the circRNA transcriptome within AD brain tissues. Specifically, we assessed circRNA expression patterns in the dorsolateral prefrontal cortex collected from nine AD-afflicted individuals and eight healthy controls. Utilising two circRNA detection tools, CIRI2 and CIRCexplorer2, we detected thousands of circRNAs and performed a differential expression analysis. CircRNAs which exhibited statistically significantly differential expression were identified as AD-specific differentially expressed circRNAs. Notably, our investigation revealed 120 circRNAs with significant upregulation and 1325 circRNAs displaying significant downregulation in AD brains when compared to healthy brain tissue. Additionally, we explored the expression profiles of the linear RNA counterparts corresponding to differentially expressed circRNAs in AD-afflicted brains and discovered that the linear RNA counterparts exhibited no significant changes in the levels of expression. We used CRAFT tool to predict that circUBE4B had potential to target miRNA named as hsa-miR-325-5p, ultimately regulated CD44 gene. This study provides a comprehensive overview of differentially expressed circRNAs in the context of AD brains, underscoring their potential as molecular biomarkers for AD. These findings significantly enhance our comprehension of AD's underlying pathophysiological mechanisms, offering promising avenues for future diagnostic and therapeutic developments., (© 2024. The Author(s).)

Objective: To study the effect of β-sheet blocking peptide H102 on the expression of AMPK-mTOR autophagy pathway-related protein in APP/PS1 double transgenic AD mice., Methods: Thirty male APP/PS1 transgenic male AD mice of 6 months old were randomly divided into AD group and H102 intervention group, and C57BL/6J male mice of the same age were used as control group (n=15). The mice in the HF group were administered with 5 μl (5.8 mg/kg) of H102 polypeptide solution through the nasal cavity at the same time period, and the mice in the control group and the AD group were given the same amount of blank adjuvant solution daily. The memory recognition ability was tested by a new object recognition experiment 30 days after continuous administration. Immunohistochemistry and Western blot were used to detect the expressions of phosphorylated AMP-activated protein kinase(P-AMPK),phosphorylated mammalian target of rapamycin (P-mTOR) and ratio of LC32to LC31(LC3II/I )in brain tissue., Results: Compared with the control group, the new object recognition index (RI) of the AD group was significantly lower (P＜0.05), and the P-AMPK and LC3II/I ratios in the brain of the mice were significantly lower (P＜0.05). The expression of P-mTOR protein was increased significantly (P＜0.05). Compared with the AD group, the RI of the H102 intervention group was increased significantly (P＜0.05), and the P-AMPK and LC3II/I ratios in the brain tissue of the mice were increased significantly (P＜0.05). The expression of P-mTOR protein was decreased significantly (P＜0.05)., Conclusion: H102 can improve the recognition and memory ability of AD mice by activating the AMPK-mTOR autophagy-related pathway.

Objective: To investigate the effect of β-sheet breaker peptide H102 on APP associated secretase in the hippocampus brain regions of APP/PS1 double transgenic mice(AD mice)., Methods: Thirty 6-month-old APP/PS1 double transgenic mice were randomly divided into AD group and H102 group, a group of C57BL/6J mice with the same age, number and background was set as controls( n =15). H102 (5.8 mg/kg) 5 μl was infused by intranasal administration to mice in H102 treatment group, and equal volume of blank solution of H102 was given to mice in control group and AD group. The ability of spatial reference memory was tested by Morris water maze after 30 days of treatment. And then immunohistochemistry tests and Western blot were used to detect the content of α-secretase (ADAM10, ADAM17), β-secretase (BACE1), γ-secretase (PS1, APH1a, PEN2) in the hippocampus brain regions., Results: Compared with the control group, the expression of BACE1, PS1, PEN-2 and APH1-a protein in the hippocampus of AD group were significantly increased, ADAM10, ADAM17 protein expression were significantly reduced ( P <0.05); Compared with the model group, H102 could significantly improve the spatial learning and memory ability of AD mice, significantly decreased the expression of BACE1, PS1, PEN-2 and APH1-a protein in the hippocampus, significantly increased the expression of ADAM10 and ADAM17 protein( P <0.05)., Conclusions: β sheet peptides blocked H102 can reduce the formation of Aβ in the hippocampus brain area, improve the activity of α-secretase in the hippocampus brain region, decrease the activity of β-and γ-secretase, improve the learning and memory ability of AD mice.

β-amyloid hypothesis is the predominant hypothesis in the study of pathogenesis of Alzheimer's disease. This hypothesis claims that aggregation and neurotoxic effects of amyloid β (Aβ) is the common pathway in a variety of etiological factors for Alzheimer's disease. Aβ peptide derives from amyloid precursor protein (APP). β-sheet breaker peptides can directly prevent and reverse protein misfolding and aggregation in conformational disorders. Based on the stereochemical structure of Aβ1-42 and aggregation character, we had designed a series of β-sheet breaker peptides in our previous work and screened out a 10-residue peptide β-sheet breaker peptide, H102. We evaluated the effects of H102 on expression of P-tau, several associated proteins, inflammatory factors and apoptosis factors, and examined the cognitive ability of APP transgenic mice by behavioral test. This study aims to validate the β-amyloid hypothesis and provide an experimental evidence for the feasibility of H102 treatment for Alzheimer's disease.

Objective: To study the effect of combining the injection of beta-sheet breaker H102 with human umbilical cord mesenchymal stem cell (hUCMSC) on APP transgenic mice behavior, P-tau, apoptosis and the expression of relevant enzymes in the brain., Methods: APP transgenic mice were randomly divided into model group, hUCMSC group, H102 group, H102 with hUCMSC group and a group of C57BL/6J mice with the same age and background was set as normal. After two weeks and four weeks, the ability of spatial reference memory was tested by Morris Water Maze. After four weeks, immunohistochemical stain and Western blot were done to detect the content of Bad, Bax, Bcl-2, Bcl-xl, P-tau, GSK-3beta, PP-2A and PP-1 in mice brain., Results: The ability of memory of hUCMSC in 2 weeks group was slightly improved than that in the model group. hUCMSC in four weeks group, H102 group and H102 with hUCMSC group significantly improved the ability of and memory, and reduced the phosphorylation of tau and brain cell's apoptosis of the Alzheimer disease (AD) mice., Conclusion: Beta-sheet breaker H102 together with transplanting hUCMSC is an effective therapeutic strategy for AD.