Cardona Eric A, Wu Zheng, Bolton Blythe M, Cenik Elif Sarinay, Pierce Jonathan T
Department of Neuroscience, Center for Learning and Memory, University of Texas at Austin, Austin, TX.
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX.
bioRxiv. 2025 May 15:2025.05.06.652574. doi: 10.1101/2025.05.06.652574.
Alzheimer's disease (AD) causes a characteristic spatiotemporal pattern of neurodegeneration, resulting in the loss of associated faculties such as cognition. The factors which account for this pattern of degeneration are unclear, as AD risk genes are numerous and often broadly expressed. Previously, we generated a model of AD using the nematode in which the AD risk variant of apolipoprotein E, , is pan-neuronally expressed. We showed that HSN class motor neurons degenerate in early adult. Here, we expand on our past work by performing behavioral analyses to deduce the effect of APOE4 on the function of distinct neuronal circuits. We found evidence that APOE4 induces dysfunction of other neurons; this spatiotemporal pattern of degeneration roughly correlates with endogenous levels of PTL-1, the homolog of human MAPT also known as tau. Moreover, deletion of suppressed defects in multiple behaviors, suggesting broad protective effects across the nervous system including the HSN neurons. Lastly, we show that PTL-1 in the touch receptor neurons, where PTL-1 is most abundant, is required cell nonautonomously for degeneration of the HSN neurons. Our results suggest that may provide a useful system to study how endogenous Tau acts downstream of APOE4 to cause progressive, patterned neurodegeneration.
阿尔茨海默病（AD）会引发一种具有特征性的神经变性时空模式，导致认知等相关功能丧失。导致这种变性模式的因素尚不清楚，因为AD风险基因众多且通常广泛表达。此前，我们利用线虫构建了一个AD模型，其中载脂蛋白E的AD风险变体ε4在全神经元中表达。我们发现HSN类运动神经元在成年早期会发生变性。在此，我们通过进行行为分析来拓展以往的研究工作，以推断APOE4对不同神经回路功能的影响。我们发现有证据表明APOE4会诱导其他神经元功能障碍；这种变性的时空模式大致与PTL-1的内源性水平相关，PTL-1是人类MAPT（也称为tau）的同源物。此外，删除ptl-1可抑制多种行为缺陷，表明其对包括HSN神经元在内的整个神经系统具有广泛的保护作用。最后，我们表明，在触觉感受神经元中含量最为丰富的PTL-1，对于HSN神经元的变性而言，其细胞非自主性是必需的。我们的研究结果表明，线虫可能为研究内源性Tau如何在APOE4下游发挥作用以导致进行性、有模式的神经变性提供一个有用的系统。
