Zerbi Valerio, Wiesmann Maximilian, Emmerzaal Tim L, Jansen Diane, Van Beek Maarten, Mutsaers Martina P C, Beckmann Christian F, Heerschap Arend, Kiliaan Amanda J
Departments of Anatomy, Donders Institute for Brain Cognition and Behaviour, Radiology.
Departments of Anatomy, Donders Institute for Brain Cognition and Behaviour, Geriatric Medicine, and.
J Neurosci. 2014 Oct 15;34(42):13963-75. doi: 10.1523/JNEUROSCI.0684-14.2014.
It is well established that the cholesterol-transporter apolipoprotein ε (APOE) genotype is associated with the risk of developing neurodegenerative diseases. Recently, brain functional connectivity (FC) in apoE-ε4 carriers has been investigated by means of resting-state fMRI, showing a marked differentiation in several functional networks at different ages compared with carriers of other apoE isoforms. The causes of such hampered FC are not understood. We hypothesize that vascular function and synaptic repair processes, which are both impaired in carriers of ε4, are the major contributors to the loss of FC during aging. To test this hypothesis, we integrated several different MRI techniques with immunohistochemistry and investigated FC changes in relation with perfusion, diffusion, and synaptic density in apoE4 and apoE-knock-out (KO) mice at 12 (adult) and 18 months of age. Compared with wild-type mice, we detected FC deficits in both adult and old apoE4 and apoE-KO mice. In apoE4 mice, these changes occurred concomitant with increased mean diffusivity in the hippocampus, whereas perfusion deficits appear only later in life, together with reduced postsynaptic density levels. Instead, in apoE-KO mice FC deficits were mirrored by strongly reduced brain perfusion since adulthood. In conclusion, we provide new evidence for a relation between apoE and brain connectivity, possibly mediated by vascular risk factors and by the efficiency of APOE as synaptic modulator in the brain. Our results show that multimodal MR neuroimaging is an excellent tool to assess brain function and to investigate early neuropathology and aging effects in translational research.
胆固醇转运蛋白载脂蛋白ε（APOE）基因型与神经退行性疾病的发病风险相关，这一点已得到充分证实。最近，通过静息态功能磁共振成像（fMRI）对载脂蛋白E-ε4携带者的脑功能连接（FC）进行了研究，结果显示，与其他载脂蛋白E亚型携带者相比，不同年龄的ε4携带者在多个功能网络中存在明显差异。这种FC受损的原因尚不清楚。我们假设，血管功能和突触修复过程在ε4携带者中均受损，它们是衰老过程中FC丧失的主要原因。为了验证这一假设，我们将几种不同的磁共振成像（MRI）技术与免疫组织化学相结合，研究了12个月（成年）和18个月大的载脂蛋白E4和载脂蛋白E基因敲除（KO）小鼠的FC变化与灌注、扩散和突触密度的关系。与野生型小鼠相比，我们在成年和老年载脂蛋白E4和载脂蛋白E-KO小鼠中均检测到FC缺陷。在载脂蛋白E4小鼠中，这些变化与海马体平均扩散率增加同时发生，而灌注缺陷仅在生命后期出现，同时突触后密度水平降低。相反，在载脂蛋白E-KO小鼠中，自成年期起FC缺陷就伴随着脑灌注的显著降低。总之，我们为载脂蛋白E与脑连接之间的关系提供了新证据，这种关系可能由血管危险因素以及载脂蛋白E作为脑内突触调节剂的效率介导。我们的结果表明，多模态磁共振神经成像在转化研究中是评估脑功能、研究早期神经病理学和衰老效应的极佳工具。
