Paradis E, Douillard H, Koutroumanis M, Goodyer C, LeBlanc A
The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, The Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Canada.
J Neurosci. 1996 Dec 1;16(23):7533-9. doi: 10.1523/JNEUROSCI.16-23-07533.1996.
Neuronal apoptosis is a suspected cause of neurodegeneration in Alzheimer's disease (AD). Increased levels of amyloid beta peptide (Abeta) induce neuronal apoptosis in vitro and in vivo. The underlying molecular mechanism of Abeta neurotoxicity is not clear. The normal concentration of Abeta in cerebrospinal fluid is 4 nM. We treated human neuron primary cultures with 100 nM amyloid beta peptides Abeta(1-40) and Abeta(1-42) and the control reverse peptide Abeta(40-1). We find that although little neuronal apoptosis is induced by either peptide after 3 d of treatment, Abeta(1-42) provokes a rapid and sustained downregulation of a key anti-apoptotic protein, bcl-2, whereas it increases levels of bax, a protein known to promote cell death. In contrast, the Abeta(1-40) downregulation of bcl-2 is gradual, although the levels are equivalent to those of Abeta(1-42)-treated neurons by 72 hr of treatment. Abeta(1-40) does not upregulate bax levels. The control, reverse peptide Abeta(40-1), does not affect either bcl-2 or bax protein levels. In addition, we found that the Abeta(1-40)- and Abeta(1-42)- but not Abeta(40-1)-treated neurons had increased vulnerability to low levels of oxidative stress. Therefore, we propose that although high physiological amounts of Abeta are not sufficient to induce apoptosis, Abeta depletes the neurons of one of its anti-apoptotic mechanisms. We hypothesize that increased Abeta in individuals renders the neurons vulnerable to age-dependent stress and neurodegeneration.
神经元凋亡被怀疑是阿尔茨海默病（AD）神经退行性变的一个原因。β淀粉样肽（Aβ）水平升高在体外和体内均可诱导神经元凋亡。Aβ神经毒性的潜在分子机制尚不清楚。脑脊液中Aβ的正常浓度为4 nM。我们用100 nM的淀粉样β肽Aβ（1-40）和Aβ（1-42）以及对照反向肽Aβ（40-1）处理人原代神经元培养物。我们发现，虽然处理3天后两种肽诱导的神经元凋亡都很少，但Aβ（1-42）能迅速且持续地下调一种关键的抗凋亡蛋白bcl-2，而它会增加促细胞死亡蛋白bax的水平。相比之下，Aβ（1-40）对bcl-2的下调是渐进的，尽管到处理72小时时其水平与Aβ（1-42）处理的神经元相当。Aβ（1-40）不会上调bax水平。对照反向肽Aβ（40-1）不影响bcl-2或bax蛋白水平。此外，我们发现Aβ（1-40）和Aβ（1-42）处理的神经元（而非Aβ（40-1）处理的神经元）对低水平氧化应激的易感性增加。因此，我们提出，虽然生理水平的高剂量Aβ不足以诱导凋亡，但Aβ会耗尽神经元的一种抗凋亡机制。我们推测，个体中Aβ增加会使神经元易受年龄依赖性应激和神经退行性变的影响。
