RESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Ratones , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Ratones Transgénicos , Esfingomielina Fosfodiesterasa/genética , Modelos Animales de Enfermedad , Inmunoterapia , Precursor de Proteína beta-AmiloideRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Neuropatología/métodos , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Memoria , Ratones , Plasticidad Neuronal , Neuronas/metabolismo , Receptores de Ghrelina/metabolismo , Esfingomielina Fosfodiesterasa/genética , Esfingomielina Fosfodiesterasa/metabolismoRESUMEN
PURPOSE: We measured the umbilical cord arterial concentrations of isoprostane(8-iso-PGF2alpha) and intended to decide whether the umbilical cord arterial concentrations of isoprostane could be used as a useful parameter for lipid peroxidation in newborn infants. METHODS: The isoprostane and malondialdehyde(MDA) concentrations of the umbilical cord were measured by enzyme immunoassay and TBARS(thiobarbituric acid reactive substance) assay in 33 preterm and 28 term infants, respectively. The concentrations of isoprostane and MDA were compared between preterm infants and term infants, and were analysed for association with perinatal risk factors and neonatal complications. RESULTS: Umbilical cord arterial concentrations of isoprostane were 704.7+/-635.6 pg/mL and 421.9+/-306.5 pg/mL in preterm and term infants, respectively. Umbilical cord arterial concentrations of MDA were 44.0+/-22.9 micrometer/L and 26.2+/-10.7 micrometer/L in preterm and term infants, respectively. Umbilical cord arterial concentrations of isoprostane and MDA in preterm infants were significantly higher than those in term infants(P<0.05). The umbilical cord arterial concentrations of isoprostane were significantly associated with perinatal risk factors such as fetal distress, oligohydramnios, and breech delivery in preterm infants and pregnancy-induced hypertension in term infants(P<0.05). CONCLUSION: Umbilical cord arterial concentrations of isoprostane in preterm infants were higher than those in term infants, and those are significantly associated with some perinatal risk factors.
