| Abstrakt: |
Nicole Delatorre & Hannah Van Rossum are co‐first authors Background: Neuroinflammation is a well‐documented feature of Alzheimer's Disease (AD). Two important questions in defining the role of the neuroimmune system in AD remain unaddressed: 1) the initiation phase of inflammation and 2) sex differences in the inflammatory cascade. Previous preclinical findings from our group demonstrated elevated inflammatory and immune transcripts including CD3, CD4, and MHCII. With this work, we extend and translate our preclinical discoveries to test the hypotheses that the inflammatory phenotype of LOAD is initiated in midlife of the human aging process and sex differences are prevalent. Method: Both fixed and frozen human tissue samples were obtained from NIH NeuroBioBank (University of Maryland, University of Miami, and Mt. Sinai) that included the corpus callosum, hippocampus, and hypothalamus of 40 brain donors that were sex and age matched. For the purposes of this study, samples were sub‐classified into 3 groups: healthy aging 40‐49 years‐old, healthy aging 50‐59 years‐old, and AD age 60‐80 years‐old. Transcriptomic analyses were conducted to determine neuroinflammatory gene expression and to identify common signaling profiles. Neuroinflammatory markers were visualized using 3,3'‐diaminobenzidine immunohistochemistry and included microglia (IBA‐1), activated microglia (HLA), and T‐cells (CD3, CD4, CD8). Result: Gene expression change was determined by comparing each group to the young male. The profiles were compared using fisher exact tests and revealed region‐specific and sex‐specific transcript regulation. Midlife females exhibited significant differences in genes involved in hypothalamic adaptive immune response (p=0.0054), hippocampal astrocyte function p=0.007, and hypothalamic inflammatory signaling p=0.028). AD males exhibited altered gene expression in corpus callosum neurotransmission (p=0.0355), hippocampal innate immune response, and hypothalamic adaptive and innate immune response (p=0.0496, p=0.0208). Both midlife female and AD male showed hippocampal upregulation of innate immune transcripts and hypothalamic upregulation of adaptive and innate immune response genes. Conclusion: These results provide evidence of early activation of the immune response in brain as a potential sex‐dependent risk factor for AD. Outcomes of these analyses support future studies that identify neuroimmune biomarkers of the AD prodrome and present an early opportunity for intervention in order to reduce risk and/or delay AD. NIH: R01AG057931, R01AG057931‐02S1, T32AG061897, R01AG057931‐01A1 [ABSTRACT FROM AUTHOR] |
