Quantifying scaling exponents for neurite morphology of in vitro-cultured human iPSC-derived neurons using discrete Loewner evolution: A statistical-physical approach to the neuropathology in Alzheimer's disease.

Defining the morphological disorders causing neurodegenerative diseases is an unresolved problem. In this study, we propose a statistical-physical approach to quantify neurite morphology and evaluate the pathological states induced by Alzheimer's disease (AD). We analyzed the two-dimensional morphologies of neurites of in vitro-cultured human induced-pluripotent stem cell-derived neurons, reprogrammed from both a healthy person and a patient with AD, using discrete chordal Loewner evolution. For the numerically calculated Loewner driving forces, detrended fluctuation analysis was performed, and the morphological characteristics of the neurites were quantified using short-range and long-range scaling exponents. The day in vitro (DIV)-dependent behaviors of the scaling exponents and the associated neurite-type categorizations suggested that differences between healthy and AD neurites can be observed from the early stage (DIV3) of their development. Notably, AD neurites have less long-range autocorrelations than healthy neurites, particularly in the earlier stages (DIV3-10). Immunofluorescence-staining results suggested that these differences precede significant expressions of ß-amyloid and phosphorylated tau, which are known as biological factors causing AD. We expect that these results will lead to a theoretical interpretation of the neurogenerative disease, providing the physical properties of individual neurites with different morphologies.

Decreased Plasma Octanoylated Ghrelin Levels in Mice by Oleanolic Acid.

Ghrelin is a stomach-derived peptide hormone with an appetite-stimulating effect. Octanoylation on the serine-3 residue of ghrelin by ghrelin O-acyl transferase (GOAT) is essential for its orexigenic effect. Mature octanoylated ghrelin is generated by the C-terminal cleavage of octanoylated proghrelin via prohormone convertases (furin, PC1/3, or PC2). We previously established an AGS-GHRL8 cell line that produces octanoylated ghrelin in the presence of octanoic acid, and found that oleanolic acid suppresses octanoylated ghrelin production in AGS-GHRL8 cells. Here, we investigated the effects of oleanolic acid in C57BL/6J mice fed a standard, high-fat, or high-glucose diet. Oral administration of oleanolic acid for seven days (20 or 40 mg/kg) reduced plasma octanoylated ghrelin levels and body weight gain in the standard diet-fed mice but not in other two diet-fed mice. There were no significant differences in ghrelin, GOAT, furin, PC1/3, and PC2 gene expression levels between the vehicle- and oleanolic acid-treated mice fed a standard diet. Octanoyl-CoA is a substrate for ghrelin octanoylation by GOAT. We found that oleanolic acid did not affect octanoyl-CoA production in vitro. Hence, the inhibitory effect of oleanolic acid on octanoylated ghrelin production may not be related to the decrease in octanoyl-CoA. The results of this study may provide valuable knowledge for the development of anti-obesity agents with an inhibitory effect on octanoylated ghrelin production.