Martin L J, Pardo C A, Cork L C, Price D L
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196.
Am J Pathol. 1994 Dec;145(6):1358-81.
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)
通过免疫细胞化学和电子显微镜分析了17只年龄在10至37岁之间的猕猴的大脑皮质，以确定淀粉样前体蛋白和β-淀粉样蛋白的细胞及亚细胞定位、参与老年斑形成和β-淀粉样蛋白实质沉积的细胞成分，以及这些病变的时空发展情况。在幼年和老年猕猴中，淀粉样前体蛋白在锥体细胞和非锥体细胞体的细胞质中富集。在神经毡中，淀粉样前体蛋白在树突和树突棘中最为丰富；很少有轴突、轴突终末以及静息的星形胶质细胞和小胶质细胞含有淀粉样前体蛋白。在突触处，淀粉样前体蛋白主要存在于突触后成分中，并在不对称突触的突触后致密物中富集。与老年斑形成相关的最早形态学变化是皮质神经毡中与年龄相关的异常，其特征是在突触前终末和树突内形成致密体，以及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加。在大多数年龄大于26岁的猕猴中，新皮质实质表现出神经原纤维病变和斑块，其特征为胞质突起肿胀、神经元胞体散在分布，以及老年斑内或周边的反应性胶质细胞。这些斑块内的神经原纤维以及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，非纤维状β-淀粉样蛋白免疫反应性在神经元胞体和树突的细胞质溶酶体以及活化的星形胶质细胞和小胶质细胞的细胞体及突起中可见。在成熟斑块中，β-淀粉样蛋白免疫反应性与实质内的细胞外纤维相关；一些退化的树突和胞体的细胞质膜以及活化胶质细胞的突起显示出弥漫性细胞内β-淀粉样蛋白免疫反应性。我们得出结论，突触处的形态学异常（包括突触前和突触后成分的变化）先于淀粉样前体蛋白在神经原纤维、活化的星形胶质细胞和小胶质细胞中的积累以及细胞外纤维状β-淀粉样蛋白的沉积；含有淀粉样前体蛋白的神经元胞体/树突和反应性胶质细胞是老年斑内β-淀粉样蛋白的主要来源；在细胞外β-淀粉样蛋白沉积和β-折叠纤维形成之前，非纤维状β-淀粉样蛋白存在于神经元和非神经元细胞内。（摘要截短至400字）
