Age-dependent accumulation of tau aggregation in Caenorhabditis elegans.
Age-dependent accumulation of tau aggregation in Caenorhabditis elegans.
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DOI：
10.3389/fragi.2022.928574
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发表时间：
2022
影响因子：
--
通讯作者：
Ackley, Brian D.
中科院分区：
文献类型：
--
作者：
Nunez, Wendy Aquino;Combs, Benjamin;Gamblin, T. Chris;Ackley, Brian D.
衰老是阿尔茨海默病(AD)和相关疾病(ADRD)的主要危险因素。Tau聚集是AD和其他tau病的标志。即使在正常衰老的大脑中也发现了tau的聚集，但在疾病状态下，在突触退化和神经元丢失的大脑区域中，tau的聚集明显更多。目前尚不清楚tau聚集和衰老如何相互作用，导致在疾病状态下观察到的表型。大多数AD/ADRD动物模型都集中在tau显著聚集之后的晚期阶段。在衰老过程中，我们能观察到早期聚集事件和进展的地方很少。为了解决这一差距，我们创建了表达GFP标记版本的人类tau蛋白的线虫模型。在这里，我们研究了tau-GFP在衰老过程中的表现，比较了野生型tau(HTau40)、疾病相关突变(P301S)和易于聚集的变体(3PO)。我们测量了GFP强度随年龄的变化，并将这些变化与线虫的正常衰老联系起来。我们发现，根据所表达的tau变体的不同，tau的稳定性和积累量也不同。HTau40GFP和P301SGFP定位于轴突和胞体，3POGFP定位于胞体。3POGFP的表达导致寿命缩短和运动速度的变化，这与病理效应一致。最后，我们发现人类tau与人类tau的线虫同源基因PTL-1存在遗传上的相互作用，其中PTL-1的缺失显著加速了表达3PO的动物的死亡时间。
Aging is the primary risk factor for Alzheimer’s disease (AD) and related disorders (ADRDs). Tau aggregation is a hallmark of AD and other tauopathies. Even in normal aging, tau aggregation is found in brains, but in disease states, significantly more aggregated tau is present in brain regions demonstrating synaptic degeneration and neuronal loss. It is unclear how tau aggregation and aging interact to give rise to the phenotypes observed in disease states. Most AD/ADRD animal models have focused on late stages, after significant tau aggregation has occurred. There are fewer where we can observe the early aggregation events and progression during aging. In an attempt to address this gap, we created C. elegans models expressing a GFP-tagged version of the human tau protein. Here we examined how tau-gfp behaved during aging, comparing wild-type tau (hTau40), a disease-associated mutation (P301S), and an aggregation-prone variant (3PO). We measured age-dependent changes in GFP intensity and correlated those changes to normal aging in the nematode. We found differences in tau stability and accumulation depending on the tau variant expressed. hTau40GFP and P301SGFP were localized to axons and cell bodies, while 3POGFP was more concentrated within cell bodies. Expression of 3POGFP resulted in decreased lifespan and variations in locomotor rate, consistent with a pathological effect. Finally, we found that the human tau interacted genetically with the C. elegans ortholog of human tau, ptl-1, where the loss of ptl-1 significantly accelerated the time to death in animals expressing 3PO.
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影响因子：
6.1
作者：
Combs B;Hamel C;Kanaan NM
通讯作者：
Kanaan NM
影响因子：
--
作者：
Combs B;Tiernan CT;Hamel C;Kanaan NM
通讯作者：
Kanaan NM
影响因子：
2.9
作者：
Combs B;Gamblin TC
通讯作者：
Gamblin TC
影响因子：
9.8
作者：
David DC;Ollikainen N;Trinidad JC;Cary MP;Burlingame AL;Kenyon C
通讯作者：
Kenyon C
DOI：
10.1002/alz.12325
发表时间：
2021-06
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Datta D;Leslie SN;Wang M;Morozov YM;Yang S;Mentone S;Zeiss C;Duque A;Rakic P;Horvath TL;van Dyck CH;Nairn AC;Arnsten AFT
通讯作者：
Arnsten AFT