Caesar Ina, Nilsson K Peter R, Hammarstrom Per, Lindgren Mikael, Prokop Stefan, Heppner Frank L, Schmeidler James, Haroutunian Vahram, Holtzman David M, Hof Patrick R, Gandy Sam
Icahn School of Medicine at Mount Sinai.
Linköping University: Linkopings universitet.
Res Sq. 2023 Feb 8:rs.3.rs-2524641. doi: 10.21203/rs.3.rs-2524641/v1.
The apolipoprotein E (, gene; apoE, protein) ε4 allele is the most common identified genetic risk factor for typical late-onset sporadic Alzheimer's disease (AD). Each ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, ε3.
We have employed hyperspectral fluorescence imaging with an amyloidspecific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either ε3 or ε4.
As expected ε4/ε4 tissues had significantly larger load of CAA than ε3/ε3. isoform-dependent morphological differences in amyloid plaques were also observed. Amyloid plaques in ε3/ε3 tissue had small spherical cores and large corona while amyloid plaques in ε4/ε4 tissues had large irregular and multilobulated plaques with relatively smaller corona. Despite the different morphologies of their cores, the p-FTAA stained ε3/ε3 amyloid plaque cores had spectral properties identical to those of ε4/ε4 plaque cores.
These data support the hypothesis that one mechanism by which the ε4 allele affects AD is by modulating the macrostructure of pathological protein deposits in brain. ε4 is associated with a higher density of amyloid plaques (as compared to ε3). We speculate that multilobulated -associated plaques arise from multiple initiation foci that coalesce as the plaques grow.
载脂蛋白E（基因；载脂蛋白E，蛋白质）ε4等位基因是典型晚发性散发性阿尔茨海默病（AD）最常见的已确定遗传风险因素。与参考等位基因ε3相比，每个ε4等位基因使患AD的相对风险大致增加两倍。
我们使用了一种淀粉样蛋白特异性构象传感探针p-FTAA进行高光谱荧光成像，以阐明来自纯合子为ε3或ε4的患者的人类死后AD脑组织样本的新鲜冷冻前额叶皮质样本中的蛋白质聚集体结构和形态。
正如预期的那样，ε4/ε4组织中的CAA负荷明显高于ε3/ε3。还观察到淀粉样斑块中存在异构体依赖性形态差异。ε3/ε3组织中的淀粉样斑块有小的球形核心和大的晕圈，而ε4/ε4组织中的淀粉样斑块有大的不规则和多叶状斑块，晕圈相对较小。尽管它们的核心形态不同，但p-FTAA染色的ε3/ε3淀粉样斑块核心的光谱特性与ε4/ε4斑块核心的光谱特性相同。
这些数据支持以下假设，即ε4等位基因影响AD的一种机制是通过调节大脑中病理性蛋白质沉积物的宏观结构。ε4与更高密度的淀粉样斑块相关（与ε3相比）。我们推测多叶状相关斑块由多个起始灶产生，这些起始灶在斑块生长时合并。
