Masliah E, Westland C E, Rockenstein E M, Abraham C R, Mallory M, Veinberg I, Sheldon E, Mucke L
Department of Neurosciences, University of California at San Diego, La Jolla 92093-0624, U.S.A.
Neuroscience. 1997 May;78(1):135-46. doi: 10.1016/s0306-4522(96)00553-2.
The beta-amyloid protein precursor (APP) is well conserved across different species and may fulfill important physiological functions within the CNS. While high-level neuronal expression of amyloidogenic forms of human APP results in beta-amyloid production and neurodegeneration, lower levels of neuronal human APP expression in neurons of transgenic mice may primarily accentuate physiological functions of this molecule. To assess the neuroprotective potential of human APP in vivo, mice from seven distinct transgenic lines expressing different human APP isoforms from the neuron-specific enolase promoter were challenged with systemic kainate injections (n=30) or transgene-mediated glial expression of gp120 (n=32), an HIV-1 protein capable of inducing excitotoxic neuronal damage. To quantitate human APP-mediated neuroprotection. the area of neuropil occupied by presynaptic terminals and neuronal dendrites in the neocortex and hippocampus of each mouse was determined using laser scanning confocal microscopy of double-immunolabelled brain sections and computer-aided image analysis. Compared with gp120 singly transgenic controls, mice from three of three human APP751gp120 bigenic lines expressing the 751 amino acid form of human APP at low levels showed significant protection against degeneration of presynaptic terminals; two of these lines also showed significantly less damage to neuronal dendrites. Two of three human APP695/gp120 bigenic lines expressing human APP695 at low levels were protected against presynaptic and dendritic damage, whereas one low expressor line and a human APP695/gp120 bigenic line expressing human APP695 at higher levels showed no significant protection. In the corresponding human APP singly transgenic lines, overexpressing only specific human APP isoforms, significant protection against kainate-induced degeneration of presynaptic terminals and neuronal dendrites was found in two of three human APP751 lines and not in any of the four human APP695 lines tested. These results indicate that human APP can protect neurons against chronic and acute excitotoxic insults in vivo and that human APP isoforms differ in their neuroprotective potential, at least with respect to specific forms of neural injury. It is therefore possible that impairments of neuroprotective human APP functions or aberrant shifts in human APP isoform ratios could contribute to neurodegeneration.
β-淀粉样蛋白前体（APP）在不同物种间高度保守，可能在中枢神经系统中发挥重要的生理功能。虽然人APP淀粉样生成形式的高水平神经元表达会导致β-淀粉样蛋白产生和神经退行性变，但转基因小鼠神经元中人APP的低水平表达可能主要增强了该分子的生理功能。为了评估人APP在体内的神经保护潜力，对来自七个不同转基因品系的小鼠进行了挑战，这些品系从神经元特异性烯醇化酶启动子表达不同的人APP异构体，通过全身注射海藻酸（n = 30）或转基因介导的gp120胶质细胞表达（n = 32），gp120是一种能够诱导兴奋性毒性神经元损伤的HIV-1蛋白。为了定量人APP介导的神经保护作用，使用双免疫标记脑切片的激光扫描共聚焦显微镜和计算机辅助图像分析，确定每只小鼠新皮层和海马体中突触前终末和神经元树突所占据的神经毡面积。与单独的gp120转基因对照相比，三个表达低水平751个氨基酸形式人APP的人APP751/gp120双转基因品系中的小鼠对突触前终末的退化表现出显著的保护作用；其中两个品系对神经元树突的损伤也明显较小。三个表达低水平人APP695的人APP695/gp120双转基因品系中的两个对突触前和树突损伤具有保护作用，而一个低表达品系和一个表达高水平人APP695的人APP695/gp120双转基因品系则没有显著的保护作用。在相应的人APP单转基因品系中，仅过表达特定的人APP异构体，在三个表达人APP751的品系中有两个对海藻酸诱导的突触前终末和神经元树突退化具有显著的保护作用，而在所测试的四个表达人APP695的品系中均未发现这种保护作用。这些结果表明，人APP可以在体内保护神经元免受慢性和急性兴奋性毒性损伤，并且人APP异构体在神经保护潜力方面存在差异，至少在特定形式的神经损伤方面如此。因此，神经保护性人APP功能的损害或人APP异构体比例的异常变化可能导致神经退行性变。
