Niemann–Pick C1 (NPC1) mouse models show neurofibrillary tangles as do human patients. A previous study in NPC1/tau double–null mutant mice showed that tau knockout nulls and heterozygotes unexpectedly had decreased survival when compared with NPC1 single mutants (Pacheco et al., Hum Molec Genetics 18:956–965, 2009). This was done in a null model of NPC1 (Npc1^−/−). We have extended these results to a hypomorphic model (Npc1^nmf164) and additionally studied tau phosphorylation, which has not been previously done in a tau heterozygote. As before, NPC1/tau double-mutant mice had shortened survival when compared with the NPC1 single mutant. Tau dosage was not affected by the Npc1 mutation. The increased phosphorylation of tau-ser396 previously noted in NPC1 mouse models was also present, but unaffected by the tau knockout, indicating that changes in tau phosphorylation are not the cause of decreased survival in NPC1/tau double mutants. Thus, the reason for shortened survival of NPC1 mouse models with concomitant tau haploinsufficiency is uncertain.

Niemann-Pick C1（NPC1）小鼠模型显示出人类患者的神经原纤维缠结。以前在NPC1 / tau双无效突变小鼠中进行的研究表明，与NPC1单突变体相比，tau基因敲除无效位点和杂合子意外地降低了存活率（Pacheco等人，Hum Molec Genetics 18：956-965，2009）。这是在NPC1的空模型（Npc1 ^-/-）中完成的。我们已经将这些结果扩展到一个亚同型模型（Npc1 ^nmf164），并另外研究了tau磷酸化，这在tau杂合子中以前是没有的。与以前一样，与NPC1单突变体相比，NPC1 / tau双突变体小鼠的生存期缩短了。Tau剂量不受Npc1的影响突变。还存在先前在NPC1小鼠模型中提到的tau-ser396磷酸化增加，但不受tau基因敲除的影响，这表明tau磷酸化的改变并不是NPC1 / tau双重突变体存活率降低的原因。因此，不确定伴随tau单倍体功能不全的NPC1小鼠模型生存期缩短的原因。