Metabolism-Based Gene Differences in Neurons Expressing Hyperphosphorylated AT8− Positive (AT8+) Tau in Alzheimer’s Disease

Abstract

Metabolic adaptations in the brain are critical to the establishment and maintenance of normal cellular functions and to the pathological responses to disease processes. Here, we have focused on specific metabolic pathways that are involved in immune-mediated neuronal processes in brain using isolated neurons derived from human autopsy brain sections of normal individuals and individuals diagnosed as Alzheimer’s disease (AD). Laser capture microscopy was used to select specific cell types in immune-stained thin brain sections followed by NanoString technology to identify and quantify differences in mRNA levels between age-matched control and AD neuronal samples. Comparisons were also made between neurons isolated from AD brain sections expressing pathogenic hyperphosphorylated AT8- positive (AT8+) tau and non-AT8+ AD neurons using double labeling techniques. The mRNA expression data showed unique patterns of metabolic pathway expression between the subtypes of captured neurons that involved membrane based solute transporters, redox factors, and arginine and methionine metabolic pathways. We also identified the expression levels of a novel metabolic gene, Radical-S-Adenosyl Domain1 ( RSAD1) and its corresponding protein, Rsad1, that impact methionine usage and radical based reactions. Immunohistochemistry was used to identify specific protein expression levels and their cellular location in NeuN+ and AT8+ neurons. APOE4 vs APOE3 genotype-specific and sex-specific gene expression differences in these metabolic pathways were also observed when comparing neurons from individuals with AD to age-matched individuals.

Cell‐Specific Dysregulation of Iron and Oxygen Homeostasis as a Novel Pathophysiology in PSP

“…The p values were computed with nSolver and adjusted for multiple comparisons using the Benjamini‐Hochberg method. Adjusted p values were not used for thresholding differentially expressed genes, however 30 . Visual representations of gene analysis were generated using the nSolver and Graphpad Prism (version 9).…”

“…Adjusted p values were not used for thresholding differentially expressed genes, however. 30 Visual representations of gene analysis were generated using the nSolver and Graphpad Prism (version 9).…”

Functional Diversity of HemN-like Proteins

“… 94 Recently, it has been shown that the gene expression level of RSAD1 increased apparently in the brain tissues from individuals diagnosed as Alzheimer’s disease. 95 Besides the important roles of RSAD1 from animals, the members from plants also appear to be functional, as has been revealed by transcriptomic analysis. 96 In vitro studies showed that RSAD1 firmly binds heme, as a typical heme absorption spectrum was clearly observed in the human RSAD1-heme complex, 90 suggesting that RSAD1 likely has a heme chaperone activity similar to HemW.…”

“…Removing the RSAD1 gene in zebra fish embryos causes serious dysfunctional development, suggesting RSAD1 is required for survival . Recently, it has been shown that the gene expression level of RSAD1 increased apparently in the brain tissues from individuals diagnosed as Alzheimer’s disease . Besides the important roles of RSAD1 from animals, the members from plants also appear to be functional, as has been revealed by transcriptomic analysis …”

Aggregation, Transmission, and Toxicity of the Microtubule-Associated Protein Tau: A Complex Comprehension

“…A new perspective regarding tau toxicity is that it has the potential to disrupt cellular metabolism [206,207]. Tau deposition is correlated with impaired metabolisms of glucose, norepinephrine, and purine [208,209], reduced glucose utilization and oxidative phosphorylation activity [209,210], as well as the interference of the arginine, ornithine, and methionine metabolisms [211]. Although the metabolic decline in AD can be attributed to the synergistic effect of Aβ and tau [207], it is plausible that tau itself exerts a significant influence on inducing metabolic disturbances.…”