Stress, Immunity, and Alzheimer’s Disease Progression: Studies in Transgenic Mouse Models


Stress is a risk factor for several neuropsychiatric disorders and has been implicated in the pathogenesis of cognitive decline and Alzheimer’s disease (AD). It is believed the mechanisms linking stress exposure to cognitive decline are complex, and involves neuroendocrine dysregulation, inflammatory pathways, and direct neuronal damage; however, mechanism involving the immune system, remains poorly understood. There is an urgent need to understand better the mechanisms by which stress contributes to cognitive decline and AD progression because it can help in finding potential therapeutic targets. To this end, a new study published in Cell Reports and conducted by Yilin Feng, Jiaqi Fan, et al., and led by Associate Professor Shaohua Ma from Tsinghua University Shenzhen International Graduate School (SIGS), the researchers investigated how stress influences the progression of AD by using male APP/PS1 transgenic mice as a model, where the researchers dissected the specific pathways through which stress impacts AD, with a focus on immune response alterations.

First, the team subjected the mice to negative stressors such as chronic social defeat and restraint to simulate chronic stress conditions. On the other hand, some mice were exposed to environmental enrichment (EE), which they considered as a positive stressor to observe its protective effects. They assessed the impact of stress and EE on cognitive functions, by performing several behavioral tests, including the Morris Water Maze for learning and memory, the Open Field Test for anxiety, and the Forced Swim Test for depression-like behavior. Moreover, they identified molecular changes associated with stress exposure and EE by performing brain RNA sequencing which allowed the detection of differentially expressed genes and pathways involved in stress responses and AD pathology. Furthermore, to investigate the involvement of immune cells, the researchers used flow cytometry to analyze the proportions and states of immune cells, particularly CD8+ and CD4+ T cells, in the peripheral blood and brain tissues of the mice. They also measured the levels of key cytokines including interleukin-6 (IL-6) and interleukin-10 (IL-10) to understand their roles in modulating the immune response related to AD progression under stress.

The authors found negative stressors worsened cognitive impairments and accelerated the pathological features of AD, such as increased amyloid-beta accumulation. Moreover, environmental enrichment had a protective effect, slowing the progression of AD symptoms and reducing the pathological accumulation of amyloid-beta in the brain. Furthermore, exposure to stress resulted in an increased ratio of CD8+/CD4+ T cells in peripheral blood, indicating a shift towards a more cytotoxic immune environment, which is associated with worse outcomes in AD. Additionally the authors observed the environmental enrichment resulted in a more balanced immune profile with a decreased CD8+/CD4+ ratio, suggesting a protective immunomodulatory effect. IL-6 and IL-10 were also identified as key regulators in the interaction between stress and AD. Stress conditions led to increased levels of IL-6, a pro-inflammatory cytokine, and decreased levels of IL-10, an anti-inflammatory cytokine, contributing to a pro-inflammatory state conducive to AD progression. In contrast, EE was associated with lower IL-6 levels and higher IL-10 levels, promoting a healthier immune state that could potentially delay the onset or progression of AD. It is worth mentioning that the authors reported that mice exposed to chronic stress displayed poor performance in cognitive tests like the Morris Water Maze, indicating accelerated cognitive decline. Also mice in enriched environments showed better cognitive performance, suggesting that positive environmental factors can enhance cognitive resilience against AD. These findings demonstrate that both stress exposure and environmental factors significantly impact AD progression through mechanisms involving immune modulation and cytokine regulation. This comprehensive investigation provides a foundation for future therapeutic strategies aimed at mitigating the detrimental effects of stress on AD by targeting specific immune and molecular pathways. In conclusion, the new study conducted by Tsinghua SIGS scientists provides a comprehensive look at the intersection of stress, immune response, and AD progression. The thorough investigation on T cell dynamics, cytokine profiles, and the protective effects of environmental enrichment advance our understanding of AD and highlights new targets for future research and clinical interventions.

Stress, Immunity, and Alzheimer's Disease Progression: Studies in Transgenic Mouse Models - Medicine Innovates

About the author

Yilin Feng (First author of Stress regulates Alzheimer’s disease progression via selective enrichment of CD8+ T cells)

Yilin Feng is a dedicated researcher currently pursuing a PhD at Tsinghua University, focusing on brain organoids and their potential applications in the study of neurodegenerative diseases. She received her B.S. and M.D. degrees from Sun Yat-sen University, where she gained expertise in whole-cell patch-clamp technique, which sparked her interest in electrophysiology.

At Tsinghua University, Yilin worked on investigating neuro-immune interactions in Alzheimer’s disease using AD mice and brain organoids. Her major findings include elucidating the mechanism of manipulation of CD8+ T cells in AD in both in vivo and in vitro systems.

Yilin’s research interests lie at the intersection of neuroscience, immunology, and electrophysiology, with a focus on the role of microglia, adaptive immunity, and seizure activity in Alzheimer’s disease pathology. She has published high-impact research as first and co-first author in prestigious journals such as Cell Reports, Cell Physical Science, Pattern, and STAR Protocols.

About the author

Jiaqi Fan (Co-first author of Stress regulates Alzheimer’s disease progression via selective enrichment of CD8+ T cells)

Jiaqi Fan is a talented researcher currently pursuing her Ph.D. at Tsinghua University, focusing on computational neuroscience with a special interest in large-scale multimodal neural data acquisition and modeling. She received her bachelor’s degree from the Department of Automation at the University of Science and Technology of China (USTC) in 2019, where she laid a solid foundation for her future research endeavors.

During her Ph.D. studies, Jiaqi has made significant contributions to the field of neuroscience. Her innovative work on multimodal neural data acquisition and modeling has attracted the attention of the scientific community. Jiaqi’s research has been published in prestigious journals, including Patterns and Cell Reports. In addition to her co-first author publications, Jiaqi has also made valuable contributions to studies published in top journals such as Nature Methods, Nature Biotechnology, and Nature Computational Science, where she is listed as a co-author.

About the author

Dr. Shaohua Ma received his B.Eng. from Sun Yat-sen University in 2009, and Ph.D. the University of Cambridge in 2013. He did the postdoctoral training at the University of Oxford in 2013 – 2017 before joining Tsinghua University in 2017, first as an assistant professor and then associate professor (core-PI) at Tsinghua-Berkeley Shenzhen Institute (TBSI). He is now an associate professor with tenure at the Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School (SIGS). His research interests include organoids and stem cell engineering, system biology and medicine, intelligent microfluidics, and 3D bioprinting, and has contributed over 50 papers as the corresponding and first authors to these fields.


Feng Y, Fan J, Cheng Y, Dai Q, Ma S. Stress regulates Alzheimer’s disease progression via selective enrichment of CD8+ T cells. Cell Rep. 2023 ;42(10):113313. doi: 10.1016/j.celrep.2023.113313.

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