Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex.
Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex.
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发表时间：
1994-12
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通讯作者：
L. Martin;C. Pardo;L. Cork;D. Price
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作者：
L. Martin;C. Pardo;L. Cork;D. Price
用免疫细胞化学和电子显微镜对年龄10~37岁的猕猴大脑皮质进行分析，以确定淀粉样前体蛋白和β-淀粉样蛋白的细胞和亚细胞定位，β-淀粉样蛋白在衰老斑块和实质沉积形成的细胞参与者，以及这些损伤的时空发展。淀粉样前体蛋白在幼猴和老年猴的锥体和非锥体神经元胞浆中均有丰富的表达。在神经束中，淀粉样前体蛋白在树突和树突棘中含量最高；少数轴突、轴突终末和静止的星形胶质细胞和小胶质细胞含有淀粉样前体蛋白。在突触，淀粉样前体蛋白主要存在于突触后成分中，并在非对称性突触的突触后密度中得到丰富。与老年斑形成相关的最早的形态变化是皮质神经管的年龄相关性异常，其特征是突触前终末和树突内形成致密小体，淀粉样前体蛋白在星形胶质细胞和小胶质细胞中的定位增强。在大多数26岁的猕猴中，新皮质实质表现为神经炎病理和斑块，其特征是胞浆突起肿胀，神经元胞体散布，在老年斑块内或周围有反应性胶质细胞。这些斑块内的轴突、反应性星形胶质细胞和小胶质细胞富含淀粉样前体蛋白。在弥漫性斑块中，非纤维β-淀粉样蛋白免疫反应可见于神经元核膜和树突的胞浆溶酶体以及激活的星形胶质细胞和小胶质细胞的胞体和突起中。在成熟的斑块中，β-淀粉样蛋白免疫反应与实质内的细胞外纤维相关；退化的树突和体细胞的一些细胞膜以及激活的胶质细胞突起显示弥漫性的细胞内β-淀粉样蛋白免疫反应。我们的结论是，突触的形态异常(包括突触前和突触后元素的变化)先于淀粉样前体蛋白在轴突和激活的星形胶质细胞和小胶质细胞内积累以及细胞外纤维β-淀粉样蛋白的沉积；神经元核周/树突和含有淀粉样前体蛋白的反应性胶质是老年斑内β-淀粉样蛋白的主要来源；非纤维β-淀粉样蛋白在β-淀粉样蛋白出现细胞外沉积和形成β-折叠纤维之前就存在于神经元和非神经元细胞内。
The cerebral cortices of macaques (ranging in age from 10 to 37 years; n = 17) were analyzed by immunocytochemistry and electron microscopy to determine the cellular and subcellular localizations of the amyloid precursor protein and beta-amyloid protein, the cellular participants in the formation of senile plaques and parenchymal deposits of the beta-amyloid protein, and the temporal/spatial development of these lesions. Amyloid precursor protein was enriched within the cytoplasm of pyramidal and nonpyramidal neuronal cell bodies in young and old monkeys. In the neuropil, amyloid precursor protein was most abundant within dendrites and dendritic spines; few axons, axonal terminals, and resting astrocytes and microglia contained the amyloid precursor protein. At synapses, amyloid precursor protein was found predominantly within postsynaptic elements and was enriched at postsynaptic densities of asymmetrical synapses. The earliest morphological change related to senile plaque formation was an age-related abnormality in the cortical neuropil characterized by the formation of dense bodies within presynaptic terminals and dendrites and an augmented localization of the amyloid precursor protein to astrocytes and microglia. In most monkeys > 26 years of age, the neocortical parenchyma exhibited neuritic pathology and plaques characterized by swollen cytoplasmic processes, interspersed somata of neurons, and reactive glia within or at the periphery of senile plaques. Neurites and reactive astrocytes and microglia within these plaques were enriched with the amyloid precursor protein. In diffuse plaques, nonfibrillar beta-amyloid protein immunoreactivity was visualized within cytoplasmic lysosomes of neuronal perikarya and dendrites and the cell bodies and processes of activated astrocytes and microglia. In mature plaques, beta-amyloid protein immunoreactivity was associated with extracellular fibrils within the parenchyma; some cytoplasmic membranes of degenerating dendrites and somata as well as processes of activated glia showed diffuse intracellular beta-amyloid protein immunoreactivity. We conclude that morphological abnormalities at synapses (including changes in both pre- and postsynaptic elements) precede the accumulation of the amyloid precursor protein within neurites and activated astrocytes and microglia as well as the deposition of extracellular fibrillar beta-amyloid protein; neuronal perikarya/dendrites and reactive glia containing the amyloid precursor protein are primary sources of the beta-amyloid protein within senile plaques; and nonfibrillar beta-amyloid protein exists intracellularly within neurons and nonneuronal cells prior to the appearance of extracellular deposits of the beta-amyloid protein and the formation of beta-pleated fibrils.(ABSTRACT TRUNCATED AT 400 WORDS)