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敲除淀粉样前体蛋白基因促进铝诱导的小鼠认知障碍损伤
Gene knockout of amyloid precursor protein promotes aluminum-induced cognitive impairment in mice
目的 淀粉样前体蛋白(APP)基因是与痴呆症发生发展相关的重要基因，利用APP基因敲除小鼠探讨铝诱导的认知障碍损伤，及APP对中
毒性认知障碍损伤的作用。方法 3月龄同窝阴性小鼠分为野生对照组（WT）和铝处理组（WT+Al），APP敲除小鼠分为模型对照组（APP-/- ）和
模型处理组（APP-/- +Al），每组10只。铝处理组在粮食中加入相应剂量的乳酸铝，同窝阴性小鼠和APP-/-小鼠给予常规鼠粮作为对照，乳酸
铝处理8周后进行水迷宫实验。HE染色观察小鼠脑组织神经病理改变；Western blotting检测糖原合成激酶3β(GSK-3β)和Caspase-3的活性变
化。结果 与WT相比，WT+Al小鼠在原平台区域停留时间和穿越原平台区域次数减少了28.1%和18.8%，而APP-/- +Al小鼠在原平台区域停留时间
和穿越原平台区域次数减少了44.1%和51%。Western blotting显示，WT+Al小鼠和APP-/-+Al小鼠脑组织中p-GSK-3β分别减少了17.4%和46.4%。结论 APP基因敲除促进铝诱导的神经毒性和学习记忆损伤。APP基因敲除导致GSK-3β的磷酸化水平降低、活性增高。由于GSK-3β活性增加对痴呆症具有促进作用，推测APP通过抑制GSK-3β活性在痴呆症发生过程中发挥保护效应。
Objective Amyloid precursor protein (APP) is involved in dementia, however, little is known about its role in the development of dementia. The APP knockout mice were used to investigate the effects of amyloid precursor protein on
aluminum-induced cognitive impairment in mice. Methods APP knockout mice and the littermates of no-negative mice aged 3 months were selected randomly and performed Morris water-maze tests after administration for 8 weeks. Aluminum was administrated in the diet. One group of APP knockout mice was used for vehicle group. One group of the littermates of no-negative mice was used as normal control (WT). The pathological changes in brain were detected by HE staining. The activities of glycogen synthase kinase 3β(GSK-3β)and Caspase-3 were also examined by Western blotting. Results Compared with WT mice, Al-treated WT mice exhibited a decrease in the target-quadrant abidance by 28.1% and the crossing-target number by 18.8% in the probe test; APP knockout mice administrated showed a significant decrease in the target-quadrant abidance by 44.1% and the crossing-target number by 51% in the probe test. Compared with that of WT mice, the level of p-GSK-3β was decreased by 17.4% in Al-treated WT mice and by 46.4% in Al-treated APP knockout mice. Conclusion Gene knockout of APP promotes aluminum-induced neurotoxicity and cognitive impairment in mice. APP knockout leads to a significant increase of the activity of GSK-3β, which can accelerate the processing of dementia. Thus the protective effect of APP may be through inhibiting the activity of GSK-3β.
淀粉样前体蛋白 / 铝 / 水迷宫 / 认知障 / 糖原合成激酶3 / 小鼠
Amyloid ecursor protein / Aluminum / Morris water maze / Cognitive impairment / Glycogen synthase kinase 3β / Mouse
1］Stokin GB, Lillo C, Falzone TL, et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer,s disease［J］. Science, 2005, 307 (5713): 1282-1288.
［2］Savva GM, Wharton SB, Ince PG, et al. Age, neuropathology, and dementia［J］. N Engl J Med, 2009, 360 (22): 2302-2309.
［3］Iqbal K,Grundke-Iqbal I. Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and
prevention［J］. J Cell Mol Med, 2008, 12 (1): 38-55.
［4］Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Abeta42 immunisation in Alzheimer.s disease: follow-up of a
randomised, placebo-controlled phase I trial［J］. Lancet, 2008, 372 (9634): 216-223.
［5］Mattson MP. Pathways towards and away from Alzheimer,s disease［J］. Nature, 2004, 430 (7000): 631-639.
［6］Golub MS,Keen CL. Effects of dietary aluminum on pubertal mice［J］. Neurotoxicol Teratol, 1999, 21 (5): 595-602.
［7］Ribes D, Colomina MT, Vicens P, et al. Effects of oral aluminum exposure on behavior and neurogenesis in a transgenic
mouse model of Alzheimer,s disease［J］. Exp Neurol, 2008, 214 (2): 293-300.
［8］Laczo J, Vlcek K, Vyhnalek M, et al. Spatial navigation testing discriminates two types of amnestic mild cognitive
impairment［J］. Behav Brain Res, 2009, 202 (2): 252-259.
［9］Reinhard C, Hebert SS,De Strooper B. The amyloid-beta precursor protein: integrating structure with biological function
［J］. EMBO J, 2005, 24 (23): 3996-4006.
［10］Dawson GR, Seabrook GR, Zheng H, et al. Age-related cognitive deficits, impaired long-term potentiation and reduction
in synaptic marker density in mice lacking the beta-amyloid precursor protein［J］. Neuroscience, 1999, 90 (1): 1-13.
［11］Frisardi V, Solfrizzi V, Capurso C, et al. Aluminum in the diet and Alzheimer,s disease: from current epidemiology to
possible disease-modifying treatment［J］. J Alzheimers Dis, 2010, 20 (1): 17-30.
［12］Lin R, Chen X, Li W, et al. Exposure to metal ions regulates mRNA levels of APP and BACE1 in PC12 cells: blockage by
curcumin［J］. Neurosci Lett, 2008, 440 (3): 344-347.
［13］Tanino H, Shimohama S, Sasaki Y, et al. Increase in phospholipase C-delta1 protein levels in aluminum-treated rat brains
［J］. Biochem Biophys Res Commun, 2000, 271 (3): 620-625.
［14］Steinbrecher KA, Wilson W, Cogswell PC, et al. Glycogen synthase kinase 3beta functions to specify gene-specific,
NF-kappaB-dependent transcription［J］. Mol Cell Biol, 2005, 25 (19): 8444-8455.
［15］Liu SJ, Zhang AH, Li HL, et al. Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase
and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory［J］. J Neurochem, 2003, 87
(6): 1333-1344.
［16］Zeng YQ, Chen XCh, Huang Ch, et al. The attenuation of β-amyloid peptide25-35 -induced tau hyperphosporylation in cortical
neurons by the regulation of ginsenoside Rg1 on the activity of GSK-3β and PP2A［J］. Acta Anatomica Sinica, 2007, 38
(6): 665-670.(in Chinese)
曾育琦, 陈晓春, 黄春, 等. 人参皂苷Rg1通过调节GSK-3β/PP2A活性减轻皮层神经元Tau蛋白过度磷酸化［J］. 解剖学报， 2007, 38
(6): 665-670.
［17］Tomljenovic L. Aluminum and Alzheimer,s disease: after a century of controversy, is there a plausible link［J］? J
Alzheimers Dis, 2011, 23 (4): 567-598.
国家科技支撑计划课题(2012BA139B02)和国家“重大新药创制”科技重大专项课题（课题编号2011ZX09307-302
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