Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aß uptake in astrocytes.

The link between changes in astrocyte function and the pathological progression of Alzheimer's disease (AD) has attracted considerable attention. Interestingly, activated astrocytes in AD show abnormalities in their lipid content and metabolism. In particular, the expression of apolipoprotein E (ApoE), a lipid transporter, is decreased. Because ApoE has anti-inflammatory and amyloid ß (Aß)-metabolizing effects, the nuclear receptors, retinoid X receptor (RXR) and LXR, which are involved in ApoE expression, are considered promising therapeutic targets for AD. However, the therapeutic effects of agents targeting these receptors are limited or vary considerably among groups, indicating the involvement of an unknown pathological factor that modifies astrocyte and ApoE function. Here, we focused on the signaling lipid, sphingosine-1-phosphate (S1P), which is mainly produced by sphingosine kinase 2 (SphK2) in the brain. Using astrocyte models, we found that upregulation of SphK2/S1P signaling suppressed ApoE induction by both RXR and LXR agonists. We also found that SphK2 activation reduced RXR binding to the APOE promoter region in the nucleus, suggesting the nuclear function of SphK2/S1P. Intriguingly, suppression of SphK2 activity by RNA knockdown or specific inhibitors upregulated lipidated ApoE induction. Furthermore, the induced ApoE facilitates Aß uptake in astrocytes. Together with our previous findings that SphK2 activity is upregulated in AD brain and promotes Aß production in neurons, these results indicate that SphK2/S1P signaling is a promising multifunctional therapeutic target for AD that can modulate astrocyte function by stabilizing the effects of RXR and LXR agonists, and simultaneously regulate neuronal pathogenesis.

The Pursuit of the "Inside" of the Amyloid Hypothesis-Is C99 a Promising Therapeutic Target for Alzheimer's Disease?

Aducanumab, co-developed by Eisai (Japan) and Biogen (U.S.), has received Food and Drug Administration approval for treating Alzheimer's disease (AD). In addition, its successor antibody, lecanemab, has been approved. These antibodies target the aggregated form of the small peptide, amyloid-ß (Aß), which accumulates in the patient brain. The "amyloid hypothesis" based therapy that places the aggregation and toxicity of Aß at the center of the etiology is about to be realized. However, the effects of immunotherapy are still limited, suggesting the need to reconsider this hypothesis. Aß is produced from a type-I transmembrane protein, Aß precursor protein (APP). One of the APP metabolites, the 99-amino acids C-terminal fragment (C99, also called ßCTF), is a direct precursor of Aß and accumulates in the AD patient's brain to demonstrate toxicity independent of Aß. Conventional drug discovery strategies have focused on Aß toxicity on the "outside" of the neuron, but C99 accumulation might explain the toxicity on the "inside" of the neuron, which was overlooked in the hypothesis. Furthermore, the common region of C99 and Aß is a promising target for multifunctional AD drugs. This review aimed to outline the nature, metabolism, and impact of C99 on AD pathogenesis and discuss whether it could be a therapeutic target complementing the amyloid hypothesis.

Lipid flippase dysfunction as a therapeutic target for endosomal anomalies in Alzheimer's disease.

Endosomal anomalies because of vesicular traffic impairment have been indicated as an early pathology of Alzheimer'| disease (AD). However, the mechanisms and therapeutic targets remain unclear. We previously reported that ßCTF, one of the pathogenic metabolites of APP, interacts with TMEM30A. TMEM30A constitutes a lipid flippase with P4-ATPase and regulates vesicular trafficking through the asymmetric distribution of phospholipids. Therefore, the alteration of lipid flippase activity in AD pathology has got attention. Herein, we showed that the interaction between ßCTF and TMEM30A suppresses the physiological formation and activity of lipid flippase in AD model cells, A7, and AppNL-G-F/NL-G-F model mice. Furthermore, the T-RAP peptide derived from the ßCTF binding site of TMEM30A improved endosomal anomalies, which could be a result of the restored lipid flippase activity. Our results provide insights into the mechanisms of vesicular traffic impairment and suggest a therapeutic target for AD.

TiO2-supported Au144 nanoclusters for enhanced sonocatalytic performance.

The production of reactive oxygen species (ROS), such as hydroxyl radicals, by ultrasonic activation of semiconductor nanoparticles (NPs), including TiO2, has excellent potential for use in sonodynamic therapy and for the sonocatalytic degradation of pollutants. However, TiO2 NPs have limitations including low yields of generated ROS that result from fast electron-hole recombination. In this study, we first investigated the sonocatalytic activity of TiO2-supported Au nanoclusters (NCs) (Au NCs/TiO2) by monitoring the production of hydroxyl radicals (•OH) under ultrasonication conditions. The deposition of Au144 NCs on TiO2 NPs was found to enhance sonocatalytic activity for •OH production by approximately a factor of 2. Electron-hole recombination in ultrasonically excited TiO2 NPs is suppressed by Au144 NCs acting as an electron trap; this charge separation resulted in enhanced •OH production. In contrast, the deposition of Au25 NCs on TiO2 NPs resulted in lower sonocatalytic activity due to less charge separation, which highlights the effectiveness of combining Au144 NCs with TiO2 NPs for enhancing sonocatalytic activity. The sonocatalytic action that forms electron-hole pairs on the Au144/TiO2 catalyst is due to both heat and sonoluminescence from the implosive collapse of cavitation bubbles. Consequently, the ultrasonically excited Au144 (3 wt. %)/TiO2 catalyst exhibited higher catalytic activity for the production of •OH because of less light shadowing effect, in contrast to the lower catalytic activity when irradiated with only external light.

Cell density-dependent modulation of perlecan synthesis by dichloro(2,9-dimethyl-1,10-phenanthroline)zinc(II) in vascular endothelial cells.

Proteoglycans that are synthesized by vascular endothelial cells contribute to the proliferation, migration, and blood coagulation-fibrinolytic system in vascular endothelial cells. Clarification of the molecular mechanisms for proteoglycan synthesis allows understanding of the regulation of endothelial functions. The research strategy of bioorganometallics analyzes biological systems using organic-inorganic hybrid molecules as tools. The present study found dichloro(2,9-dimethyl-1,10-phenanthroline)zinc(II) and its ligand-modulated perlecan expression in vascular endothelial cells, which depends on the cell density.