Dues Dylan J, Nguyen An Phu Tran, Becker Katelyn, Ma Jiyan, Moore Darren J
Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
Chinese Institute for Brain Research, Beijing, China.
NPJ Parkinsons Dis. 2023 Aug 29;9(1):125. doi: 10.1038/s41531-023-00574-1.
Cognitive dysfunction is a salient feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The onset of dementia reflects the spread of Lewy pathology throughout forebrain structures. The mere presence of Lewy pathology, however, provides limited indication of cognitive status. Thus, it remains unclear whether Lewy pathology is the de facto substrate driving cognitive dysfunction in PD and DLB. Through application of α-synuclein fibrils in vivo, we sought to examine the influence of pathologic inclusions on cognition. Following stereotactic injection of α-synuclein fibrils within the mouse forebrain, we measured the burden of α-synuclein pathology at 1-, 3-, and 6-months post-injection within subregions of the hippocampus and cortex. Under this paradigm, the hippocampal CA2/3 subfield was especially susceptible to α-synuclein pathology. Strikingly, we observed a drastic reduction of pathology in the CA2/3 subfield across time-points, consistent with the consolidation of α-synuclein pathology into dense somatic inclusions followed by neurodegeneration. Silver-positive degenerating neurites were observed prior to neuronal loss, suggesting that this might be an early feature of fibril-induced neurotoxicity and a precursor to neurodegeneration. Critically, mice injected with α-synuclein fibrils developed progressive deficits in spatial learning and memory. These findings support that the formation of α-synuclein inclusions in the mouse forebrain precipitate neurodegenerative changes that recapitulate features of Lewy-related cognitive dysfunction.
认知功能障碍是帕金森病（PD）和路易体痴呆（DLB）的一个显著特征。痴呆的发生反映了路易体病理在整个前脑结构中的扩散。然而，仅路易体病理的存在对认知状态的指示作用有限。因此，目前尚不清楚路易体病理是否是导致PD和DLB认知功能障碍的实际底物。通过在体内应用α-突触核蛋白原纤维，我们试图研究病理性包涵体对认知的影响。在小鼠前脑立体定向注射α-突触核蛋白原纤维后，我们在注射后1个月、3个月和6个月测量了海马和皮质各亚区域内α-突触核蛋白病理负担。在这种模式下，海马CA2/3亚区对α-突触核蛋白病理特别敏感。令人惊讶的是，我们观察到CA2/3亚区内的病理在各时间点都大幅减少，这与α-突触核蛋白病理合并为致密的体细胞包涵体随后发生神经变性一致。在神经元丢失之前观察到银阳性的变性神经突，这表明这可能是原纤维诱导的神经毒性的早期特征以及神经变性的先兆。至关重要的是，注射α-突触核蛋白原纤维的小鼠在空间学习和记忆方面出现了渐进性缺陷。这些发现支持小鼠前脑中α-突触核蛋白包涵体的形成引发了神经退行性变化，这些变化重现了路易体相关认知功能障碍的特征。
