Accumulation of intracellular amyloid-β peptide (Aβ 1-40) in mucopolysaccharidosis brains
Accumulation of intracellular amyloid-β peptide (Aβ 1-40) in mucopolysaccharidosis brains
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DOI：
10.1097/00005072-199908000-00004
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发表时间：
1999-08-01
影响因子：
3.2
通讯作者：
Trojanowski, JQ
中科院分区：
文献类型：
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作者：
Ginsberg, SD;Galvin, JE;Trojanowski, JQ
为了评估先天性糖胺聚糖代谢缺陷引起的硫酸乙酰肝素体内积累是否会导致神经原纤维缠结和/或老年斑的形成，如阿尔茨海默病 (AD) 中所见，我们研究了 9 名年龄在 1 至 42 岁之间的粘多糖贮积症 (MPS) 患者的死后大脑。 Hurler 综合征（MPS I；n = 5）和 Sanfilippo 综合征（MPS III；n = 4）以及山羊 MPS IIID 和小鼠 MPS VII 模型患者的大脑通过硫黄素-S 染色和使用针对硫酸乙酰肝素蛋白聚糖、过度磷酸化 tau、 淀粉样蛋白 β 肽前体蛋白 (APP) 和淀粉样蛋白 β 肽（A β [1-40] 和 A β [1-42]）。还利用双位点夹心酶联免疫吸附测定 (ELISA) 来比较从 MPS 患者颞叶皮层获得的总可溶性和不溶性 Aβ (1-40) 和 Aβ (1-42) 水平。尽管在此研究的任何 MPS 大脑中均未检测到神经原纤维缠结、老年斑或 tau 阳性病变，但针对 A beta (1-40) 的抗体对 MPS 患者和山羊 MPS 模型整个大脑的细胞质进行了强烈且广泛的染色。 ELISA 测定还表明，与正常对照大脑相比，MPS 大脑中可溶性 A beta (1-40) 水平显着增加了 3 倍。因此，至少一些导致 MPS 中糖胺聚糖积累的代谢缺陷也与细胞质区室中免疫反应性 Aβ (1-40) 的增加有关，其中它们可能导致这些疾病中受影响细胞的功能障碍和死亡，但不会诱导斑块和缠结的形成。 MPS 模型可以对 Aβ 和糖胺聚糖在淀粉样变性（AD 的神经病理学特征）中所起的作用进行机制研究。
To evaluate whether in vivo accumulations of heparan sulfate caused by inborn errors in the metabolism of glycosaminoglycans lead to the formation of neurofibrillary tangles and/or senile plaques, as seen in Alzheimer disease (AD), we studied postmortem brains from 9 patients, ages 1 to 42 years, with mucopolysaccharidosis (MPS). The brains of patients with Hurler's syndrome (MPS I; n = 5) and Sanfilippo's syndrome (MPS III; n = 4) as well as from caprine MPS IIID and murine MPS VII models were evaluated by thioflavine-S staining and by immunohistochemistry using antibodies directed against heparan sulfate proteoglycans, hyperphosphorylated tau, amyloid-beta peptide precursor proteins (APP), and amyloid-beta peptides (A beta [1-40], and A beta [1-42]). A two-site sandwich enzyme-linked immunosorbent assay (ELISA) was also utilized to compare levels of total soluble and insoluble A beta (1-40) and A beta (1-42) obtained from temporal cortex of MPS patients. Although no neurofibrillary tangles, senile plaques, or tau-positive lesions were detected in any of the MPS brains studied here, antibodies directed against A beta (1-40) intensely and diffusely stained the cytoplasm of cells throughout the brains of the MPS patients and the caprine MPS model. The ELISA assay also demonstrated a significant 3-fold increase in the level of soluble A beta (1-40) in the MPS brains compared with normal control brains. Thus, at least some of the metabolic defects that lead to accumulations of glycosaminoglycans in MPS also are associated with an increase in immunoreactive A beta (1-40) within the cytoplasmic compartment where they could contribute to the dysfunction and death of affected cells in these disorders, but not induce the formation of plaques and tangles. Models of MPS may enable mechanistic studies of the role A beta and glycosaminoglycans play in the amyloidosis that is a neuropathological feature of AD.