Huang F, Buttini M, Wyss-Coray T, McConlogue L, Kodama T, Pitas R E, Mucke L
Gladstone Institute of Neurological Disease, Department of Neurology, University of California, San Francisco, USA.
Am J Pathol. 1999 Nov;155(5):1741-7. doi: 10.1016/S0002-9440(10)65489-2.
The class A scavenger receptor (SR) is expressed on reactive microglia surrounding cerebral amyloid plaques in Alzheimer's disease (AD). Interactions between the SR and amyloid beta peptides (Abeta) in microglial cultures elicit phagocytosis of Abeta aggregates and release of neurotoxins. To assess the role of the SR in amyloid clearance and Abeta-associated neurodegeneration in vivo, we used the platelet-derived growth factor promoter to express human amyloid protein precursors (hAPPs) in neurons of transgenic mice. With increasing age, hAPP mice develop AD-like amyloid plaques. We bred heterozygous hAPP (hAPP(+/-)) mice that were wild type for SR (SR(+/+)) with SR knockout (SR(-/-)) mice. Crosses among the resulting hAPP(+/-)SR(+/-) offspring yielded hAPP(+/-) and hAPP(-/-) littermates that were SR(+/+) or SR(-/-). These second-generation mice were analyzed at 6 and 12 months of age for extent of cerebral amyloid deposition and loss of synaptophysin-immunoreactive presynaptic terminals. hAPP(-/-)SR(-/-) mice showed no lack of SR expression, plaque formation, or synaptic degeneration, indicating that lack of SR expression does not result in significant accumulation of endogenous amyloidogenic or neurotoxic factors. In hAPP(+/-) mice, ablation of SR expression did not alter number, extent, distribution, or age-dependent accumulation of plaques; nor did it affect synaptic degeneration. Our results do not support a critical pathogenic role for microglial SR expression in neurodegenerative alterations associated with cerebral beta amyloidosis.
A类清道夫受体（SR）在阿尔茨海默病（AD）中围绕脑淀粉样斑块的反应性小胶质细胞上表达。小胶质细胞培养物中SR与淀粉样β肽（Aβ）之间的相互作用引发Aβ聚集体的吞噬作用和神经毒素的释放。为了评估SR在体内淀粉样蛋白清除和Aβ相关神经退行性变中的作用，我们使用血小板衍生生长因子启动子在转基因小鼠的神经元中表达人淀粉样蛋白前体（hAPPs）。随着年龄的增长，hAPP小鼠会出现类似AD的淀粉样斑块。我们将SR为野生型（SR(+/+)）的杂合hAPP（hAPP(+/-)）小鼠与SR基因敲除（SR(-/-)）小鼠进行杂交。所得hAPP(+/-)SR(+/-)后代之间的杂交产生了SR(+/+)或SR(-/-)的hAPP(+/-)和hAPP(-/-)同窝小鼠。在6个月和12个月龄时对这些第二代小鼠进行分析，以检测脑淀粉样蛋白沉积程度和突触素免疫反应性突触前终末的丧失情况。hAPP(-/-)SR(-/-)小鼠未表现出SR表达缺失、斑块形成或突触变性，这表明SR表达缺失不会导致内源性淀粉样生成或神经毒性因子的显著积累。在hAPP(+/-)小鼠中，SR表达的缺失并未改变斑块的数量、程度、分布或年龄依赖性积累；也未影响突触变性。我们的结果不支持小胶质细胞SR表达在与脑β淀粉样变性相关的神经退行性改变中起关键致病作用。
