Amorim João A, Canas Paula M, Tomé Angelo R, Rolo Anabela P, Agostinho Paula, Palmeira Carlos M, Cunha Rodrigo A
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Portugal.
J Alzheimers Dis. 2017;60(2):525-536. doi: 10.3233/JAD-170356.
Mitochondrial dysfunction is proposed to trigger memory deficits and synaptic damage at the onset of Alzheimer's disease (AD). However, it is unknown how mitochondria dysfunction might trigger synaptotoxicity and if a differential susceptibility of mitochondria located in synapses underlies the greater glutamatergic than GABAergic synaptotoxicity in early AD. Hippocampal synaptosomes (purified synapses) of a rat model of early AD, typified by selective memory deficits two weeks after intracerebroventricular injection of amyloid-β peptides (Aβ1-42, 2 nmol), simultaneously displayed three mitochondria-associated deleterious alterations: 1) hampered metabolism (decreased MTT reduction); 2) increased oxygen radical production (increased hydrogen peroxide production); 3) increased caspase-3 activity. The direct exposure of hippocampal synaptosomes to Aβ1-42 (500 nM) similarly decreased mitochondrial membrane potential (TMRM+ fluorescence) and increased mitochondria-derived oxygen radicals (MitoTraker®red-CM-H2Xros fluorescence) in individual glutamatergic (vesicular glutamate transporter-immunopositive) and GABAergic (vesicular GABA transporter-immunopositive) synaptosomes. However, significantly more glutamatergic than GABAergic synaptosomes were endowed with mitochondria (Tom20-immunopositive). These results indicate that dysfunctional mitochondria located in synapses can trigger synaptotoxicity through multifaceted mechanisms and that it is not the susceptibility of mitochondria to Aβ but more likely a different impact of dysfunctional mitochondria that underlies the greater sensitivity to synaptotoxicity of glutamatergic than GABA synapses in early AD.
线粒体功能障碍被认为是在阿尔茨海默病（AD）发病时引发记忆缺陷和突触损伤的原因。然而，尚不清楚线粒体功能障碍如何引发突触毒性，以及早期AD中谷氨酸能突触毒性大于GABA能突触毒性是否是由于突触中线粒体的不同易感性所致。早期AD大鼠模型的海马突触体（纯化的突触），以脑室内注射淀粉样β肽（Aβ1-42，2 nmol）两周后出现选择性记忆缺陷为典型特征，同时表现出三种与线粒体相关的有害改变：1）代谢受阻（MTT还原减少）；2）氧自由基产生增加（过氧化氢产生增加）；3）caspase-3活性增加。将海马突触体直接暴露于Aβ1-42（500 nM）同样会降低单个谷氨酸能（囊泡谷氨酸转运体免疫阳性）和GABA能（囊泡GABA转运体免疫阳性）突触体中的线粒体膜电位（TMRM+荧光），并增加线粒体衍生的氧自由基（MitoTraker®red-CM-H2Xros荧光）。然而，谷氨酸能突触体中含有线粒体（Tom20免疫阳性）的比例明显高于GABA能突触体。这些结果表明，突触中的功能失调线粒体可通过多方面机制引发突触毒性，并且在早期AD中，谷氨酸能突触对突触毒性的更高敏感性并非源于线粒体对Aβ的易感性，而更可能是功能失调线粒体的不同影响所致。
