Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Neuron. 2023 Oct 18;111(20):3176-3194.e7. doi: 10.1016/j.neuron.2023.07.005. Epub 2023 Aug 4.
Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.
早老素突变改变γ-分泌酶的活性会导致家族性阿尔茨海默病(AD),而载脂蛋白 E4(apoE4)是胆固醇转运的载脂蛋白,易患散发性 AD。散发性和家族性 AD 都以突触功能障碍为特征。γ-分泌酶是否参与胆固醇代谢,以及这种参与是否影响突触功能尚不清楚。在这里,我们表明在人类神经元中,慢性药理学或遗传抑制γ-分泌酶会增加突触数量,但会降低突触前释放概率,从而降低突触传递,而不会改变树突或轴突分支。为了寻找这些突触损伤的机制,我们发现慢性γ-分泌酶抑制可显著降低神经元中的胆固醇水平,但不会降低神经胶质细胞中的胆固醇水平,这反过来又刺激神经元特异性胆固醇合成基因表达。HMG-CoA 还原酶抑制剂(他汀类药物)抑制胆固醇水平可损害突触功能,类似于 γ-分泌酶抑制。因此,γ-分泌酶通过维持胆固醇水平来实现突触功能,而慢性抑制γ-分泌酶则通过降低胆固醇水平来损害突触。