Low-dose IL-2 treatment rescues cognitive deficits by repairing the imbalance between Treg and Th17 cells at the middle Alzheimer’s disease stage

Background

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by neuronal damage, amyloid plaque deposition, and chronic inflammation in the central nervous system (CNS). These pathological changes lead to gradual loss of cognitive function and destruction of brain tissue. Although the specific mechanisms causing neurodegeneration are not fully understood, increasing evidence suggests that the immune system, especially T lymphocytes, plays an important role in the pathogenesis of AD.

Paper Source

This article was published in the Journal of Neuroimmune Pharmacology, titled “Low-dose IL-2 treatment rescues cognitive deficits by repairing the imbalance between Treg and Th17 cells at the middle Alzheimer’s disease stage”. The authors include Lin Yuan, Lei Xie, Hao Zhang, Yu Zhang, Yunbo Wei, Jinhong Feng, Li Cui, Rui Tian, Jia Feng, and Di Yu, from Hubei University for Nationalities, Qilu University of Technology, Shandong University, and the University of Queensland. The article was published online in November 2023.

Experimental Procedures

Animal Model and Treatment

The study used 6-month-old Alzheimer’s disease transgenic mice (APP/PS1) and age-matched C57BL/6 mice. During the experiment, after seven days of adaptation in a specific pathogen-free (SPF) environment, mice were given 30,000 IU of human recombinant IL-2 or PBS control via intraperitoneal injection every two days for 3 months.

Flow Cytometry Analysis and Preparation of Cell Suspensions

Mice were anesthetized and peripheral spleen cells and brain tissues were collected through cardiac perfusion. Single-cell suspensions were prepared using 70-micron nylon cell strainers and a series of enzymatic digestion and separation steps. Different T cell subsets were labeled and analyzed using flow cytometry.

Immunohistochemical Analysis

After anesthesia, mice were sequentially perfused with PBS and 4% paraformaldehyde (PFA). Brains were removed and routine paraffin sections were prepared. Immunofluorescence staining was performed using specific antibodies against Aβ and CD68, and brain sections were observed under a fluorescence microscope.

Behavioral Tests

The Morris water maze test was used to assess the learning and memory abilities of mice. The test included platform localization training and probe tests after platform removal, recording escape latency, time spent in the target quadrant, and exploration path.

Data Analysis

SPSS software was used for statistical analysis of data, with one-way ANOVA and two-way repeated measures ANOVA for inter-group comparisons.

Research Results

Changes in Treg and Th17 Cell Ratios

The study found that during the progression of AD in mice, there was a significant imbalance in the ratio of Treg (regulatory T cells) to Th17 (IL-17 secreting helper T cells) in both the periphery and the brain. Specifically, the proportion of Treg cells in AD mice significantly decreased at 9 months, while the proportion of Th17 cells increased, indicating severe immune imbalance at the middle stage of the disease.

Effects of Low-dose IL-2 Treatment

Through intraperitoneal injection of low-dose IL-2, it was found that the proportion of Treg cells significantly increased in both the periphery and brain of AD mice, while the proportion of Th17 cells significantly decreased. Low-dose IL-2 treatment also adjusted the levels of Treg and Th17 related cytokines in AD mice both systemically and in the brain, significantly inhibiting the production of IL-17A and IL-22, while promoting the production of TGF-β and IL-10.

Improvement in Cognitive Function

Through the Morris water maze test, it was found that low-dose IL-2 treatment could improve the cognitive function of AD mice, including shortening of escape latency and increase in exploration path and time spent in the target quadrant.

Changes in Amyloid Pathology and Inflammatory Response

Immunohistochemical analysis showed that after low-dose IL-2 treatment, the Aβ plaque load in the brains of AD mice was significantly reduced. In addition, significantly reduced microglial activation and peripheral immune cell infiltration were observed in mice treated with low-dose IL-2, indicating a reduced neuroinflammatory response.

Conclusion

This study reveals that at the middle stage of Alzheimer’s disease, low-dose IL-2 treatment can alleviate neuroinflammation, reduce Aβ plaque deposition, and improve cognitive function by repairing the imbalance between Treg and Th17 cells. These results provide strong support for the potential application of low-dose IL-2 in the treatment of Alzheimer’s disease.

Research Significance

The results indicate that low-dose IL-2 treatment is not only effective in the early stages of AD but also shows therapeutic potential in the middle stage. This finding provides important evidence for further clinical evaluation of low-dose IL-2 treatment for AD and may extend to other brain pathologies associated with immune imbalance.

This paper provides a new perspective for understanding the pathogenesis of AD and its relationship with the immune system, while also providing a theoretical basis for developing innovative immunotherapeutic approaches for AD.

Research Highlights

1. Imbalance of Treg and Th17 cells in AD progression: This study systematically reveals for the first time the changes of Treg and Th17 cells during AD progression, especially the severe imbalance in the middle stage.

2. Therapeutic potential of low-dose IL-2: The experiment verified the effect of low-dose IL-2 in improving cognitive function, alleviating neuroinflammation, and reducing Aβ deposition by regulating immune balance in the middle stage of AD, suggesting its potential clinical application value.

3. New insights into immune intervention for AD: The study further emphasizes the importance of regulating the immune system in AD treatment, especially in the middle stage, suggesting the need for more similar immune intervention strategies.

Other Important Information

This research was supported and collaborated by multiple research institutions including Hubei University for Nationalities, Qilu University of Technology, and the University of Queensland.

Conclusion

This paper demonstrates through animal experiments that low-dose IL-2 treatment can alleviate neuroinflammation and improve cognitive function by repairing the imbalance between Treg and Th17 cells in the middle stage of Alzheimer’s disease, providing new ideas and potential clinical solutions for AD immunotherapy. This brings new hope for the treatment of middle-stage AD patients, while expanding the application prospects of low-dose IL-2 in the treatment of immune-related brain diseases.