Su J H, Cummings B J, Cotman C W
Institute for Brain Aging and Dementia, University of California Irvine, 92717-4550, USA.
Acta Neuropathol. 1998 Nov;96(5):463-71. doi: 10.1007/s004010050920.
Plaque-associated dystrophic neurites are a common pathological feature in the brains of patients with Alzheimer's disease (AD). In the present study, we investigated the relative abundance and progressive transformation of the amyloid precursor protein (APP), neurofilament (NF) and paired helical filament (PHF) tau-positive dystrophic neurites, within plaques in non-demented controls versus plaque-associated dystrophic neurites in mild or severe AD using double and triple immunolabeling. We also determined the argentophilia of the various sub-populations of dystrophic neurites. In aged non-demented brain, approximately half of the APP-positive plaques contained NF-immunopositive dystrophic neurites; rarely were PHF/tau-positive dystrophic neurites detectable. In contrast, in the AD brain, three-fourths of the APP-positive plaques contained NF-positive dystrophic neurites and half contained PHF/tau neurites. We also observed focal patches of hyper-phosphorylated NF and/or PHF/tau within APP-immunopositive dystrophic neurites, which appeared similar to retrograde degeneration, whereas we never observed focal accumulations of APP within NF- or PHF/tau-positive fibers. We hypothesize that plaque-associated dystrophic neurites within plaques develop in a particular sequence: APP-positive dystrophic neurites appear first and are non-argentophilic. This is followed by the appearance of NF-positive dystrophic neurites, where a subset of NF-positive dystrophic neurites are lightly argentophilic. Over time, PHF/tau-positive dystrophic neurites develop and are strongly argentophilic. These data suggest that dystrophic neurites can develop retrogradely from focal plaque damage to induce somatic and dendritic degeneration and potentially contribute to neurofibrillary tangle formation.
与斑块相关的营养不良性神经突是阿尔茨海默病（AD）患者大脑中的常见病理特征。在本研究中，我们使用双重和三重免疫标记，研究了非痴呆对照者斑块内淀粉样前体蛋白（APP）、神经丝（NF）和成对螺旋丝（PHF）tau阳性营养不良性神经突的相对丰度和渐进性转变，以及轻度或重度AD患者中与斑块相关的营养不良性神经突。我们还确定了不同亚群营养不良性神经突的嗜银性。在老年非痴呆大脑中，约一半的APP阳性斑块含有NF免疫阳性的营养不良性神经突；很少能检测到PHF/tau阳性的营养不良性神经突。相比之下，在AD大脑中，四分之三的APP阳性斑块含有NF阳性的营养不良性神经突，一半含有PHF/tau神经突。我们还在APP免疫阳性的营养不良性神经突内观察到了高磷酸化NF和/或PHF/tau的局灶性斑块，这似乎类似于逆行性变性，而我们从未在NF或PHF/tau阳性纤维内观察到APP的局灶性积聚。我们推测，斑块内与斑块相关的营养不良性神经突按特定顺序发展：APP阳性的营养不良性神经突首先出现且无嗜银性。随后出现NF阳性的营养不良性神经突，其中一部分NF阳性的营养不良性神经突轻度嗜银。随着时间的推移，PHF/tau阳性的营养不良性神经突发展并具有强嗜银性。这些数据表明，营养不良性神经突可从局灶性斑块损伤逆行发展，诱导躯体和树突变性，并可能导致神经原纤维缠结的形成。
