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.