Differential effects within mouse brain based on the clinical and genetic characteristics of elderly plasma

Abstract

Cognitive impairment refers to a condition where cognitive functions such as memory, attention, perception, inference, and problem-solving are compromised. Cognitive disorders, such as dementia, pose significant social and economic challenges in aging societies. However, the precise underlying mechanisms are not yet fully understood. Recent research suggests the potential involvement of blood factors in the onset and exacerbation of cognitive impairment. Nevertheless, whether blood-induced changes in brain function accompany synaptic alterations and the impact of patient characteristics beyond ageing remain unclear. I hypothesized that blood induces brain changes and that these changes vary based on cognitive function and genetic traits. In this study, I compared the plasma effect of elderly individuals with cognitive impairment to cognitively normal elderly individuals, regardless of the presence of the dementia risky gene, APOE4. I observed that the plasma from individuals with cognitive impairment, even without the APOE4 gene, adversely affected the cognitive behavior of mice when compared to plasma from cognitively normal elderly individuals. Additionally, plasma from elderly individuals carrying the APOE4 gene showed impairments in exploration behavior and NMDA receptor-associated synaptic plasticity in the hippocampus. Transcriptome and post-translational modification analyses of mouse brains revealed distinct synaptic changes depending on the presence of cognitive impairment and the APOE4 gene. Specifically, transcriptome analysis showed minimal synaptic changes induced by plasma from cognitive impairment patients with the APOE4 gene, whereas plasma from cognitive impairment patients without the APOE4 gene induced active synaptic changes. Conversely, phosphoprotein analysis demonstrated robust changes in synaptic phosphorylation for both groups. Furthermore, plasma from cognitive impairment patients with the APOE4 gene increased the expression of phosphorylated tau protein in mouse brains and decreased the expression of phosphorylated NMDA receptor protein. These findings suggest that the plasma of cognitive impairment patients directly induces synaptic changes and cognitive dysfunction. The direction and extent of these changes may vary based on patient characteristics such as cognitive function and genetic traits.