Impact of APOE genotype on prion-type propagation of tauopathy.
Impact of APOE genotype on prion-type propagation of tauopathy.
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DOI：
10.1186/s40478-022-01359-y
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发表时间：
2022-04-19
影响因子：
7.1
通讯作者：
Chakrabarty, Paramita
中科院分区：
文献类型：
--
作者：
Williams, Tristan;Ruiz, Alejandra Jolie;Ruiz, Angelica Maria;Vo, Quan;Tsering, Wangchen;Xu, Guilian;McFarland, Karen;Giasson, Benoit, I;Sullivan, Patrick;Borchelt, David R.;Chakrabarty, Paramita
载脂蛋白（APOE）是阿尔茨海默病（AD）的主要危险因素，其中E2、E3和E4同种型差异性地调节AD相关神经病理学的负担，例如淀粉样蛋白β和tau蛋白。在AD中，病理性tau被认为遵循朊病毒样机制沿着沿着神经解剖学连接扩散。为了深入了解APOE亚型是否差异调节tau蛋白的朊病毒性质并确定tau蛋白病的跨突触传递，我们产生了携带人APOE（APOE 2、APOE 3或APOE 4）或小鼠Apoe等位基因的人P301 S突变tau转基因小鼠（PS19）。小鼠在幼年时接受预先形成的K18-tau聚集体的脑内注射，在接种后5个月进行分析。与具有小鼠Apoe等位基因的亲本PS19小鼠相比，表达人APOE等位基因的PS19小鼠通常对K18-tau接种有更强烈的AT 8免疫反应性磷酸化tau病理学反应。APOE 3纯合子小鼠相对于APOE 2或APOE 4纯合子（E3 > E4~2）积累了更高水平的AT 8反应性ptau和小胶质细胞增生。APOE 3杂合子的PS19小鼠显示出类似的结果，尽管程度较低。在我们研究的时间范围内，我们没有观察到人APOE纯合子PS19小鼠中嗜银或MC 1反应性神经元tau缠结的显著诱导。据我们所知，这是第一个全面的研究啮齿动物模型，提供了神经病理学的见解，剂量依赖性影响的APOE亚型对磷酸化的tau病理重组tau朊病毒诱导。在线版本包含补充材料，可在10.1186/s40478-022-01359-y获得。
Apolipoprotein (APOE) is a major risk factor of Alzheimer’s disease (AD), with the E2, E3 and E4 isoforms differentially regulating the burden of AD-associated neuropathologies, such as amyloid β and tau. In AD, pathological tau is thought to spread along neuroanatomic connections following a prion-like mechanism. To provide insights into whether APOE isoforms differentially regulate the prion properties of tau and determine trans-synaptic transmission of tauopathy, we have generated human P301S mutant tau transgenic mice (PS19) that carry human APOE (APOE2, APOE3 or APOE4) or mouse Apoe allele. Mice received intrahippocamal injections of preformed aggregates of K18-tau at young ages, which were analyzed 5 months post-inoculation. Compared to the parental PS19 mice with mouse Apoe alleles, PS19 mice expressing human APOE alleles generally responded to K18-tau seeding with more intense AT8 immunoreactive phosphorylated tau athology. APOE3 homozygous mice accumulated higher levels of AT8-reactive ptau and microgliosis relative to APOE2 or APOE4 homozygotes (E3 > E4~2). PS19 mice that were heterozygous for APOE3 showed similar results, albeit to a lesser degree. In the timeframe of our investigation, we did not observe significant induction of argentophilic or MC1-reactive neurofibrillary tau tangle in PS19 mice homozygous for human APOE. To our knowledge, this is the first comprehensive study in rodent models that provides neuropathological insights into the dose-dependent effect of APOE isoforms on phosphorylated tau pathology induced by recombinant tau prions. The online version contains supplementary material available at 10.1186/s40478-022-01359-y.
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