Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore.
Memory Aging and Cognition Centre, National University Health System, Kent Ridge, Singapore.
Brain Pathol. 2019 Jan;29(1):63-74. doi: 10.1111/bpa.12631. Epub 2018 Oct 17.
Alzheimer's disease (AD) is characterized by accumulation of β-amyloid plaques (AP) and neurofibrillary tangles (NFT) in the cortex, together with synaptic loss and amyloid angiopathy. Perturbations in the brain lysosomal system, including the cathepsin family of proteases, have been implicated in AD where they may be involved in proteolytic clearance of misfolded and abnormally aggregated peptides. However, the status of cathepsin D (catD) is unclear in Lewy body dementia, the second most common form of neurodegenerative dementia after AD, and characterized by Lewy bodies (LB) containing aggregated α-synuclein. Furthermore, earlier reports of catD changes in AD have not been entirely consistent. We measured CatD immunoreactivities in the temporal (Brodmann area BA21) and parietal (BA40) cortices of well characterized AD brains as well as two clinical subtypes of Lewy body dementia, namely Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), known to show varying degrees of concomitant AD pathology. Increased catD immunoreactivities in AD were found for both neocortical regions measured, where they also correlated with neuropathological NFT scores and phosphorylated pSer396 tau burden, and appeared to co-localize at least partly to NFT-containing neurons. In contrast, catD was increased only in BA40 in DLB and not at all in PDD, did not correlate with LB scores, and did not appreciably co-localize with α-synuclein inclusions. Our study suggests that catD upregulation may be an adaptive response to AD-related processes leading to neurofibrillary degeneration, but may not be directly associated with formation of α-synuclein inclusions in Lewy body dementia.
阿尔茨海默病（AD）的特征是β-淀粉样斑块（AP）和神经原纤维缠结（NFT）在皮质中的积累，以及突触丧失和淀粉样血管病。脑溶酶体系统的紊乱，包括组织蛋白酶家族的蛋白酶，与 AD 有关，它们可能参与了错误折叠和异常聚集肽的蛋白水解清除。然而，在路易体痴呆（Lewy body dementia，仅次于 AD 的第二常见神经退行性痴呆类型）中，组织蛋白酶 D（catD）的状态尚不清楚，其特征是含有聚集α-突触核蛋白的路易体（LB）。此外，AD 中 catD 变化的早期报道并不完全一致。我们在经过充分特征描述的 AD 大脑的颞叶（布罗德曼区 21 区，BA21）和顶叶（BA40）皮质中测量了 CatD 免疫反应性，以及两种临床亚型的路易体痴呆，即帕金森病痴呆（PDD）和路易体痴呆（DLB），已知它们表现出不同程度的 AD 病理共存。在测量的两个新皮质区域中，AD 中 catD 免疫反应性增加，它们还与神经病理学 NFT 评分和磷酸化 pSer396 tau 负担相关，并且似乎至少部分与 NFT 神经元共存。相比之下，在 DLB 中，只有 BA40 中的 catD 增加，而在 PDD 中则完全没有增加，与 LB 评分无关，并且与 α-突触核蛋白包涵体的共定位不明显。我们的研究表明，catD 的上调可能是对导致神经纤维变性的 AD 相关过程的适应性反应，但可能与路易体痴呆中α-突触核蛋白包涵体的形成没有直接关系。
