- 作者列表："Yoo HS","Lee S","Chung SJ","Lee YH","Ye BS","Sohn YH","Yun M","Lee PH
OBJECTIVE:To investigate the relationship between β-amyloid (Aβ) deposition and striatal dopamine depletion, cognitive functions, and neuropsychiatric symptoms in dementia with Lewy bodies (DLB). METHODS:We consecutively recruited 51 patients with DLB who had undergone a neuropsychological test, Neuropsychiatric Inventory assessment, brain MRI, N-(3-[18F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) PET, and 18F-florbetaben PET within 6 months. The patients were divided into Aβ-negative (DLB-Aβ-, n = 20) and Aβ-positive (DLB-Aβ+, n = 31) groups according to the brain amyloid plaque load score. We performed comparative analyses of dopamine transporter (DAT) activity, neuropsychological profile, and neuropsychiatric symptoms between the 2 groups. RESULTS:Compared to the DLB-Aβ- group, the DLB-Aβ+ group had a younger age at diagnosis (p = 0.017), poorer performance in attention (p = 0.028) and visuospatial (p = 0.006) functions, and higher proportion of anxiety (p = 0.006) and total neuropsychiatric burden (p = 0.013). Those in the DLB-Aβ+ group also had lower DAT activity in the anterior putamen (p = 0.015) and ventral striatum (p = 0.006) regardless of age, sex, and years of education. In addition, lower DAT activity in the ventral striatum was significantly associated with anxiety and total neuropsychiatric burden in DLB. CONCLUSIONS:This study demonstrated that Aβ deposition in DLB is associated with diagnosis at a younger age, higher cognitive and neuropsychiatric burden, and decreased DAT activity, suggesting that evaluation of clinical features and DAT activity can predict the presence of Aβ in DLB.
目的: 探讨路易体痴呆 (DLB) 患者 β-淀粉样蛋白 (a β) 沉积与纹状体多巴胺耗竭、认知功能及神经精神症状的关系。 方法: 我们连续招募了 51 例 DLB 患者，他们接受了神经心理测试、神经精神量表评估、脑 MRI 、 N-(3-[18F] 氟丙基)-2 β-碳乙氧基-3 β-(4-碘苯基) PET，以及 6 个月内的 18f-florbetaben PET。将患者分为 a β 阴性 (DLB-a β，n = 20) 和 a β 阳性 (DLB-a β +，n = 31) 各组根据脑淀粉样斑块负荷评分。我们对 2 组之间的多巴胺转运蛋白 (DAT) 活性、神经心理学特征和神经精神症状进行了比较分析。 结果: 与 DLB-a β 组相比，DLB-a β + 组诊断时年龄较小 (p = 0.017)，注意力表现较差 (p = 0.028) 和视觉空间 (p = 0.006) 的功能，和较高的比例焦虑 (p = 0.006) 和总神经精神负担 (p = 0.013)。DLB-a β + 组的前壳核 (p = 0.015) 和腹侧纹状体 (p = 0.006) 的 DAT 活性也较低，与年龄、性别无关。和多年的教育。此外，腹侧纹状体中较低的 DAT 活性与 DLB 的焦虑和总神经精神负担显著相关。 结论: 本研究证明 DLB 中的 a β 沉积与年轻时的诊断、较高的认知和神经精神负担以及 DAT 活性降低有关, 提示评价临床特征和 DAT 活性可预测 DLB 中 a β 的存在。
METHODS::Identifying disease-causing pathways and drugs that target them in Parkinson's disease (PD) has remained challenging. We uncovered a PD-relevant pathway in which the stress-regulated heterodimeric transcription complex CHOP/ATF4 induces the neuron prodeath protein Trib3 that in turn depletes the neuronal survival protein Parkin. Here we sought to determine whether the drug adaptaquin, which inhibits ATF4-dependent transcription, could suppress Trib3 induction and neuronal death in cellular and animal models of PD. Neuronal PC12 cells and ventral midbrain dopaminergic neurons were assessed in vitro for survival, transcription factor levels and Trib3 or Parkin expression after exposure to 6-hydroxydopamine or 1-methyl-4-phenylpyridinium with or without adaptaquin co-treatment. 6-hydroxydopamine injection into the medial forebrain bundle was used to examine the effects of systemic adaptaquin on signaling, substantia nigra dopaminergic neuron survival and striatal projections as well as motor behavior. In both culture and animal models, adaptaquin suppressed elevation of ATF4 and/or CHOP and induction of Trib3 in response to 1-methyl-4-phenylpyridinium and/or 6-hydroxydopamine. In culture, adaptaquin preserved Parkin levels, provided neuroprotection and preserved morphology. In the mouse model, adaptaquin treatment enhanced survival of dopaminergic neurons and substantially protected their striatal projections. It also significantly enhanced retention of nigrostriatal function. These findings define a novel pharmacological approach involving the drug adaptaquin, a selective modulator of hypoxic adaptation, for suppressing Parkin loss and neurodegeneration in toxin models of PD. As adaptaquin possesses an oxyquinoline backbone with known safety in humans, these findings provide a firm rationale for advancing it towards clinical evaluation in PD.
METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.
METHODS:BACKGROUND:Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer's disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. OBJECTIVE:Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. METHODS:Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. RESULTS:pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p = 0.0373) and percent tissue loss (p = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with WT + ONO-8713 group (p = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. CONCLUSION:In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits on anatomical outcomes after stroke, mainly in APP/PS1 mice.