Lesné Sylvain, Ali Carine, Gabriel Cecília, Croci Nicole, MacKenzie Eric T, Glabe Charles G, Plotkine Michel, Marchand-Verrecchia Catherine, Vivien Denis, Buisson Alain
Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6185, Centre Cyceron, France.
J Neurosci. 2005 Oct 12;25(41):9367-77. doi: 10.1523/JNEUROSCI.0849-05.2005.
Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-beta (Abeta) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of Abeta. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-beta precursor protein (KPI-APP) followed by a shift from alpha-secretase to beta-secretase-mediated APP processing. This shift is a result of the inhibition of the alpha-secretase candidate tumor necrosis factor-alpha converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal Abeta secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase Abeta production and represent a causal risk factor for developing AD.
急性脑损伤已被确定为患阿尔茨海默病（AD）的一个风险因素。由于谷氨酸在这些病变中起关键作用，我们研究了谷氨酸受体激活对皮层神经元原代培养物中β淀粉样蛋白（Aβ）产生的影响。我们发现亚致死性N-甲基-D-天冬氨酸（NMDA）受体激活会增加Aβ的产生和分泌。这种效应之前是含神经元Kunitz蛋白酶抑制结构域（KPI）的淀粉样前体蛋白（KPI-APP）表达增加，随后是从α分泌酶介导的淀粉样前体蛋白（APP）加工向β分泌酶介导的APP加工转变。这种转变是与神经元KPI-APPs相关时α分泌酶候选肿瘤坏死因子-α转化酶（TACE）受到抑制的结果。这种KPI-APP/TACE相互作用在AD脑内也存在。因此，我们的研究结果揭示了一种将NMDA受体激活与神经元Aβ分泌联系起来的细胞机制。这些结果表明，即使是谷氨酸能神经传递的轻度失调也可能增加Aβ的产生，并代表患AD的一个因果风险因素。
