横須賀 誠

Amyloid-β (Aβ) and tau pathologies are important factors leading to neurodegeneration in Alzheimer's disease (AD); however the molecular mechanisms that link these pathologies remain unclear. Assuming that important though as yet unidentified factors inhibit/accelerate tau pathology and neuronal cell death under amyloid pathology, we sought to isolate and identify tau-interacting proteins from mouse brains with or without amyloid pathology. Among the proteins that were identified, we focused on protein arginine methyltransferase 8 (PRMT8), which interacts with tau specifically in the absence of amyloid pathology. To investigate the role of PRMT8 in the pathogenesis of AD, we conducted Prmt8 gene deletion and overexpression experiments in AppNL-G-F/MAPT double-knock-in (dKI) mice and analyzed the resulting pathological alterations. PRMT8-knockout did not alter the AD pathology in dKI mice, whereas PRMT8-overexpression promoted tau phosphorylation, neuroinflammation, and vacuole degeneration. To evaluate if such a PRMT8-induced vacuole degeneration depends on tau pathology, PRMT8 was overexpressed in tau-KO mice, which were consequently found to exhibit vacuole degeneration. In addition, proteomic analyses showed that PRMT8 overexpression facilitated the arginine methylation of vimentin. Abnormal protein methylation could be involved in PRMT8-induced brain pathologies. Taken together, PRMT8 may play an important role in the formation of tau pathology and vacuole degeneration.

We measured the regional saturation of oxygen of hemoglobin (rSO ) and the total hemoglobin index (HbI) in the brain and skeletal muscles of a conscious Harris’s Hawk by a near-infrared spectroscopy device (NIRS). The oxygenation levels of the breast were significantly lower than the cerebral parts. A flight exercise significantly increased the rSO and HbI of the breast. The breast surface temperature significantly increased in response to flight training by a thermography. NIRS enabled us to measure changes in the oxygenation levels of brain and skeletal muscles in a conscious Harris’s Hawk before and after a moving task. 2 2

Vascular endothelial growth factor-A (VEGF-A) is a principal regulator of hematopoiesis as well as angiogenesis. However, the functions of VEGF-A and its receptors (VEGFRs) in the differentiation of mast cells (MCs) in the skin remain unclear. The aim of this study was to determine the expression patterns of two VEGFRs (Flk1 and Flt1) in the skin MCs during development and maturation in rats. From the 17th days of embryonic development (E17) to 1 day after birth (Day 1), most of skin MCs were immature cells containing predominant alcian blue (AB)+ rather than safranin O (SO)+ granules (AB>SO MCs). AB>SO MC proportions gradually decreased, while mature AB<SO MC proportions increased from Day 7 to 28. Flk1+ MC proportions increased from E20 and reached to approximately 90% from Day 1 to 21, thereafter decreased to about 10% at Day 60 and 90. Flk1+ MC proportions changed almost in parallel with the numbers of MCs and Ki67+ MC proportions from E17 to Day 90. The proportions of MCs with both nuclear and cytoplasmic Flt1-immunoreactivity were markedly increased at Day 28, when the proportions of nuclear Flk1+, Ki67+, and AB>SO MCs had significantly decreased, and AB<SO MC proportions significantly increased. Considering that the main function of Flt1 is suppression of Flk1 effects, our results indicated that cross-talk between Flk1 and Flt1 regulates the proliferation and maturation of the skin MCs during late embryonic and neonatal development in rats.