Laiterä Tiina, Sarajärvi Timo, Haapasalo Annakaisa, Puli Lakshman, Kauppinen Tarja, Mäkinen Petra, Rauramaa Tuomas, Tanila Heikki, Jääskeläinen Juha E, Alafuzoff Irina, Soininen Hilkka, Leinonen Ville, Hiltunen Mikko
Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Kuopio, Finland; Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
PLoS One. 2014 Apr 3;9(4):e93717. doi: 10.1371/journal.pone.0093717. eCollection 2014.
The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated β- and γ-secretase activities in relation to amyloid-β (Aβ) pathology in the brain tissue samples collected from iNPH and AD patients. β- and γ-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable Aβ plaques, γ-secretase activity was significantly increased (∼ 1.6-fold) when compared to iNPH samples without Aβ plaques (p = 0.009). In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, β-secretase activity was unaltered in iNPH samples with or without Aβ plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased γ-secretase but not β-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like Aβ pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the Aβ pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aβ.
特发性正常压力脑积水（iNPH）与阿尔茨海默病（AD）的脑病理学潜在相似性很有趣，因此，聚焦于潜在分子机制的进一步研究可能为iNPH的鉴别诊断和治疗发展提供有价值的信息。在此，我们研究了从iNPH和AD患者收集的脑组织样本中与淀粉样β蛋白（Aβ）病理学相关的β和γ分泌酶活性。对26例疑似iNPH患者的额叶皮质活检样本以及74例AD患者和8例无神经纤维缠结病理学特征的受试者的颞下回皮质尸检组织样本进行了β和γ分泌酶活性检测。在可检测到Aβ斑块的iNPH样本中，与无Aβ斑块的iNPH样本相比，γ分泌酶活性显著增加（约1.6倍）（p = 0.009）。在AD样本中，未观察到γ分泌酶活性在疾病严重程度（根据神经纤维缠结病理学分为轻度、中度和重度AD）方面有统计学显著差异。相反，在有或无Aβ斑块的iNPH样本中，β分泌酶活性未改变，而在AD患者中，其活性随疾病严重程度显著增加。这些结果首次表明，在具有AD样Aβ病理学特征的iNPH患者额叶皮质活检样本中，γ分泌酶活性增加，而β分泌酶活性未增加。相反，在AD患者中，就神经纤维缠结病理学而言，这些分泌酶活性表现出相反的情况。尽管Aβ病理学存在相似之处，但iNPH和AD患者在负责Aβ产生的细胞机制上似乎存在显著差异。
