Kurata Tomoko, Kawarabayashi Takeshi, Murakami Tetsuro, Miyazaki Kazunori, Morimoto Nobutoshi, Ohta Yasuyuki, Takehisa Yasushi, Nagai Makiko, Ikeda Masaki, Matsubara Etsuro, Westaway David, Hyslop Peter St George, Harigaya Yasuo, Kamiya Tatsushi, Shoji Mikio, Abe Koji
Department of Neurology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
J Neurosci Res. 2007 Aug 1;85(10):2246-52. doi: 10.1002/jnr.21352.
A recent report showed that the accumulation of alpha-synuclein (alpha-syn) was detected in the brains of one-third of Alzheimer's disease and Down syndrome patients. However, the relationship between amyloid-beta protein (Abeta) and alpha-syn remains unclear. We analyzed the relation between the mutation of presenilin-1 (PS-1) and the pathological features of beta-amyloidosis and alpha-synucleinopathy. We generated doubly transgenic mice overexpressing mutant beta-amyloid precursor protein (betaAPP; Tg2576) and mutant PS-1 (PS1L286Vtg; line 198) and analyzed 19 double Tg betaAPP(+)/PS(+) mice at 5-23 months (young to old), 23 age-matched single Tg betaAPP(+)/PS(-) mice, and 11 non-Tg littermates. Immunohistochemical comparison was performed in these three groups by counting the area and the number of alpha-syn- or phosphorylated alpha-syn (palpha-syn)-positive dystrophic neurites per plaque (ASPDN, pASPDN). The acceleration of Abeta pathology was found with earlier onset and exaggerated numbers in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains. The accumulation of ASPDN and pASPDN was also accelerated in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains, especially in pASPDN. The number and area of alpha-syn and palpha-syn, and the ratio of palpha-syn positive neurites were significantly higher in double Tg betaAPP(+)/PS(+) than in single Tg betaAPP(+)/PS(-) mouse brains in middle-aged and old groups. Additional overexpression of mutant PS-1 accelerated Abeta-induced alpha-synucleinopathy and further facilitated the phosphorylation of alpha-syn, suggesting a direct association between mutant PS-1 and phosphorylation of alpha-syn.
最近的一份报告显示，在三分之一的阿尔茨海默病患者和唐氏综合征患者的大脑中检测到了α-突触核蛋白（α-syn）的积累。然而，β-淀粉样蛋白（Aβ）与α-syn之间的关系仍不清楚。我们分析了早老素-1（PS-1）突变与β-淀粉样变性和α-突触核蛋白病病理特征之间的关系。我们构建了过表达突变型β-淀粉样前体蛋白（βAPP；Tg2576）和突变型PS-1（PS1L286Vtg；198系）的双转基因小鼠，并分析了19只5至23个月（从幼年到老年）的双转基因βAPP(+)/PS(+)小鼠、23只年龄匹配的单转基因βAPP(+)/PS(-)小鼠以及11只非转基因同窝小鼠。通过计算每个斑块中α-syn或磷酸化α-syn（pα-syn）阳性营养不良性神经突的面积和数量（ASPDN、pASPDN），对这三组进行免疫组织化学比较。与单转基因βAPP(+)/PS(-)小鼠脑相比，双转基因βAPP(+)/PS(+)小鼠脑中Aβ病理变化加速，发病更早且数量更多。与单转基因βAPP(+)/PS(-)小鼠脑相比，双转基因βAPP(+)/PS(+)小鼠脑中ASPDN和pASPDN的积累也加速，尤其是pASPDN。在中年和老年组中，双转基因βAPP(+)/PS(+)小鼠脑中α-syn和pα-syn的数量、面积以及pα-syn阳性神经突的比例显著高于单转基因βAPP(+)/PS(-)小鼠脑。突变型PS-1的额外过表达加速了Aβ诱导的α-突触核蛋白病，并进一步促进了α-syn的磷酸化，表明突变型PS-1与α-syn的磷酸化之间存在直接关联。
