Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

N,N'-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer's disease transgenic mice.

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N'-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-ß (Aß) species and significantly improving cognitive function in the brains of 2 types of Alzheimer's disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aß clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment.

Gliosis in Niemann-Pick type C (NP-C) disease is characterized by marked changes in microglia and astrocytes. However, the gliosis onset and progression in NP-C has not been systematically studied, nor has the mechanism underlying this finding. Here, we found early gliosis in the subventricular zone (SVZ) of NP-C mice. Neural progenitor damage by Npc1 mutation suppressed vascular endothelial growth factor (VEGF) expression and further induced microglia activation followed by astrogliosis. Interestingly, excessive astrogliosis in the SVZ induced neural progenitor retention and/or migration into thalamus via astrocyte-derived VEGF, resulting in acceleration of thalamic and cortical gliosis through thalamo-cortical pathways. Transplantation of VEGF-overexpressing neural stem cells into the SVZ improved whole-brain pathology of NP-C mice. Overall, our data provide a new pathological perspective on NP-C neural pathology, revealing abnormalities in the subventricular-thalamo-cortical circuit of NP-C mouse brain and highlighting the importance of the SVZ microenvironment as a therapeutic target for NP-C disease.

Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer's disease.

Acid sphingomyelinase (ASM) has been implicated in neurodegenerative disease pathology, including Alzheimer's disease (AD). However, the specific role of plasma ASM in promoting these pathologies is poorly understood. Herein, we explore plasma ASM as a circulating factor that accelerates neuropathological features in AD by exposing young APP/PS1 mice to the blood of mice overexpressing ASM, through parabiotic surgery. Elevated plasma ASM was found to enhance several neuropathological features in the young APP/PS1 mice by mediating the differentiation of blood-derived, pathogenic Th17 cells. Antibody-based immunotherapy targeting plasma ASM showed efficient inhibition of ASM activity in the blood of APP/PS1 mice and, interestingly, led to prophylactic effects on neuropathological features by suppressing pathogenic Th17 cells. Our data reveals insights into the potential pathogenic mechanisms underlying AD and highlights ASM-targeting immunotherapy as a potential strategy for further investigation.

Acid sphingomyelinase inhibition improves motor behavioral deficits and neuronal loss in an amyotrophic lateral sclerosis mouse model.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of motor neurons in the spinal cord. Main symptoms are manifested as weakness, muscle loss, and muscle atrophy. Some studies have reported that alterations in sphingolipid metabolism may be intimately related to neurodegenerative diseases, including ALS. Acid sphingomyelinase (ASM), a sphingolipid-metabolizing enzyme, is considered an important mediator of neurodegenerative diseases. Herein, we show that ASM activity increases in samples from patients with ALS and in a mouse model. Moreover, genetic inhibition of ASM improves motor function impairment and spinal neuronal loss in an ALS mouse model. Therefore, these results suggest the role of ASM as a potentially effective target and ASM inhibition may be a possible therapeutic approach for ALS. [BMB Reports 2022; 55(12): 621-626].

Maximization of acoustic energy difference between two spaces.

There has recently been an increasing interest in the generation of a sound field that is audible in one spatial region and inaudible in an adjacent region. The method proposed here ensures the control of the amplitude and phase of multiple acoustic sources in order to maximize the acoustic energy difference between two adjacent regions while also ensuring that evenly distributed source strengths are used. The performance of the method proposed is evaluated by computer simulations and experiments with real loudspeaker arrays in the shape of a circle and a sphere. The proposed method gives an improvement in the efficiency of radiation into the space in which the sound should be audible, while maintaining the acoustic pressure difference between two acoustic spaces. This is shown to give an improvement of performance compared to the contrast control method previously proposed.

Bio-information scanning technology using an optical pick-up head.

We have developed a low cost and a highly compact bio-chip detection technology by modifying a commercially available optical pick-up head for CD/DVD. The highly parallel and miniaturized hybridization assays are addressed by the fluorescence emitted by the DNA-chip using the optical pick-up head. The gap between the objective lens and the bio-chip is regulated by the focus servo during the detection of the fluorescence signal. High-resolution and high-speed scanning is effectively realized by this simple scanning system instead of utilizing high-precision mechanism. Regardless of achievement of effective detection mechanism, the technique of fluorescence detection can prove to be disadvantageous because of the low stability of the dyes with low S/N ratio and an expensive setup such as a PMT detector is always required for fluorescence detection. We propose, for the first time, a novel scanning scheme based on metal nanoparticles in combination with a bio-chip substrate having a phase change recording layer. We found that the phase change process is highly affected by the existence of the densely condensed metal nanoparticles on the phase change layer during the writing process of the pick-up head.

Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM.

Although many reports have revealed dysfunction of endothelial cells in aging, resulting in blood-brain barrier (BBB) breakdown, the underlying mechanism or mechanisms remain to be explored. Here, we find that acid sphingomyelinase (ASM) is a critical factor for regulating brain endothelial barrier integrity. ASM is increased in brain endothelium and/or plasma of aged humans and aged mice, leading to BBB disruption by increasing caveolae-mediated transcytosis. Genetic inhibition and endothelial-specific knockdown of ASM in mice ameliorated BBB breakdown and neurocognitive impairment during aging. Using primary mouse brain endothelial cells, we found that ASM regulated the caveolae-cytoskeleton interaction through protein phosphatase 1-mediated ezrin/radixin/moesin (ERM) dephosphorylation and apoptosis. Moreover, mice with conditional ASM overexpression in brain endothelium accelerated significant BBB impairment and neurodegenerative change. Overall, these results reveal a novel role for ASM in the control of neurovascular function in aging, suggesting that ASM may represent a new therapeutic target for anti-aging.