Dodson Sara E, Gearing Marla, Lippa Carol F, Montine Thomas J, Levey Allan I, Lah James J
Center for Neurodegenerative Disease, Department of Neurology, Emory University Atlanta, Georgia 30322, USA.
J Neuropathol Exp Neurol. 2006 Sep;65(9):866-72. doi: 10.1097/01.jnen.0000228205.19915.20.
LR11 is an ApoE receptor that is enriched in the brain. We have shown that LR11 is markedly downregulated in patients with sporadic Alzheimer disease (AD). This finding led us to explore whether reduced LR11 expression reflects a primary mechanism of disease or merely a secondary consequence of other AD-associated changes. Therefore, LR11 expression was assessed in a transgenic mouse model of AD and familial AD (FAD) brains. Immunohistochemistry and immunoblotting of LR11 in PS1/APP transgenic and wild-type mice indicated that LR11 levels are not affected by genotype or accumulation of amyloid pathology. LR11 expression was also evaluated based on immunoblotting and LR11 immunostaining intensity in human frontal cortex in controls, sporadic AD, and FAD, including cases with presenilin-1 (PS1) and presenilin-2 (PS2) mutations. Although LR11 was reduced in sporadic AD, there was no difference in protein level or staining intensity between control and FAD cases. The finding that LR11 expression is unaffected in both a mouse model of AD and autosomal-dominant forms of AD suggests that LR11 is not regulated by amyloid accumulation or other AD neuropathologic changes. We hypothesize that LR11 loss may be specific to sporadic AD and influence amyloid pathology through mechanisms independent of substrate-enzyme interactions regulated by FAD mutations.
LR11是一种在大脑中富集的载脂蛋白E受体。我们已经表明，LR11在散发性阿尔茨海默病（AD）患者中显著下调。这一发现促使我们探究LR11表达降低是反映了疾病的主要机制，还是仅仅是其他与AD相关变化的次要结果。因此，在AD转基因小鼠模型和家族性AD（FAD）大脑中评估了LR11的表达。对PS1/APP转基因小鼠和野生型小鼠的LR11进行免疫组织化学和免疫印迹分析表明，LR11水平不受基因型或淀粉样病理积累的影响。还基于免疫印迹和对照、散发性AD和FAD患者（包括早老素-1（PS1）和早老素-2（PS2）突变病例）的人类额叶皮质中的LR11免疫染色强度评估了LR11的表达。尽管散发性AD中LR11减少，但对照和FAD病例之间的蛋白质水平或染色强度没有差异。LR11表达在AD小鼠模型和常染色体显性AD形式中均未受影响这一发现表明，LR11不受淀粉样蛋白积累或其他AD神经病理变化的调节。我们推测，LR11缺失可能是散发性AD特有的，并通过独立于FAD突变调节的底物-酶相互作用的机制影响淀粉样病理。
