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Article History

Received: 2 January 2025

Revised: 22 June 2025

Accepted: 19 November 2025

First Online: 3 December 2025

Declarations

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: All animal care and experimental procedures adhered to the guidelines set forth by the Animal Care and Use Committee of Xuzhou Medical University, under the laboratory animal ethics number: (Experimental Animal Ethics number: 202209S042). We confirm that the experimental protocol was approved by the designated institution and that all experimental animals were performed in accordance with the relevant guidelines and regulations. All animals were raised in the SPF animal laboratory of Xuzhou Medical University, using feed and clean water, and enjoying humanistic care.

: The authors declare no conflict of interest. We confirm the publication of this article.

: During the process of animal selection, we strictly adhered to the “3R” principle, namely Replacement, Reduction, and Refinement. Meanwhile, the main reasons for our selection of A53T mice for the initial behavioral assessment to establish the baseline are as follows: 1. A gradually progressive pathological process that is more in line with the natural course of human PD. The A53T mutation leads to the abnormal aggregation of α-Syn, eventually forming Lewy body-like inclusions, which is closer to the pathological processes of both sporadic PD and hereditary PD. The changes in cognitive function are usually accompanied by chronic processes such as α-Syn pathological accumulation, synaptic damage, and neuroinflammation, making it suitable for long-term tracking of the progression of cognitive impairment. α-Syn deposition also occurs in cognitive-related brain regions such as the cerebral cortex and hippocampus, so it can better study Parkinson’s disease-related cognitive impairment. 2. The mechanism of the occurrence of cognitive impairment is more similar to that of human PD. Research has shown that the A53T mutation can lead to synaptic dysfunction in multiple brain regions such as the prefrontal cortex, hippocampus, and striatum, which can better reflect the cognitive function impairment in PD patients. It is suitable for long-term follow-up and intervention studies: Cognitive assessments can be carried out at multiple time points to observe the progression of cognitive function. 3. However, the cognitive impairment in the MPTP model mainly results from the indirect effects of striatal DA depletion, and it has less impact on higher cognitive brain regions such as the prefrontal cortex and hippocampus. Since MPTP-induced damage occurs rapidly (usually within a few days to weeks), it is difficult to conduct long-term cognitive assessments. In this experiment, male mice were used mainly because the hormonal levels of female mice fluctuate with the estrous cycle, which leads to high variability in experimental results. Physiologically, there are differences between female and male mice, which can affect the effectiveness of model establishment and susceptibility. To make the results more accurate and reasonable, male mice were therefore used in the experiment.

: We confirm that the study was reported with the ARRIVE guidelines.

: The authors declare no competing financial interests.