Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits.
Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits.
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DOI：
10.1111/acel.12775
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发表时间：
2018-08
期刊：
影响因子：
7.8
通讯作者：
Oddo S
中科院分区：
文献类型：
--
作者：
Velazquez R;Ferreira E;Tran A;Turner EC;Belfiore R;Branca C;Oddo S
错误折叠和过度磷酸化的tau在几种神经退行性疾病中积累，包括阿尔茨海默病、额颞叶痴呆伴帕金森综合征、皮质基底节变性、进行性核上性麻痹、唐氏综合征和皮克病。Tau是一种微管结合蛋白，其在微管稳定中的作用已明确定义。相比之下，虽然越来越多的证据表明tau蛋白也参与突触生理学，但对成年大脑中tau蛋白功能的完整评估受到tau基因敲除小鼠中其他微管结合蛋白的强大发育补偿的阻碍。为了规避这些发育补偿并评估tau在成人大脑中的作用，我们产生了表达靶向tau的多西环素诱导型短发夹（Sh）RNA的腺相关病毒（AAV），本文称为AAV-ShRNATau。我们在7个月大的C57 B16/SJL野生型小鼠中用AAV-ShRNATau或对照AAV进行双侧立体定位注射。我们发现，急性敲低成年海马中的tau蛋白会显著损害运动协调和空间记忆。阻断AAV-ShRNATau的表达，从而使tau水平恢复到对照水平，恢复了运动协调和空间记忆。从机制上讲，降低的tau水平与较低的BDNF水平、与学习相关的突触蛋白水平降低以及棘密度降低相关。我们提供了令人信服的证据，证明tau蛋白对于成年大脑中的运动和认知功能是必要的，从而坚定地支持tau蛋白功能丧失可能导致许多tau蛋白病的临床表现。这些发现具有深远的临床意义，因为抗tau治疗正在进行阿尔茨海默病的临床试验。
Misfolded and hyperphosphorylated tau accumulates in several neurodegenerative disorders including Alzheimer's disease, frontotemporal dementia with Parkinsonism, corticobasal degeneration, progressive supranuclear palsy, Down syndrome, and Pick's disease. Tau is a microtubule‐binding protein, and its role in microtubule stabilization is well defined. In contrast, while growing evidence suggests that tau is also involved in synaptic physiology, a complete assessment of tau function in the adult brain has been hampered by robust developmental compensation of other microtubule‐binding proteins in tau knockout mice. To circumvent these developmental compensations and assess the role of tau in the adult brain, we generated an adeno‐associated virus (AAV) expressing a doxycycline‐inducible short‐hairpin (Sh) RNA targeted to tau, herein referred to as AAV‐ShRNATau. We performed bilateral stereotaxic injections in 7‐month‐old C57Bl6/SJL wild‐type mice with either the AAV‐ShRNATau or a control AAV. We found that acute knockdown of tau in the adult hippocampus significantly impaired motor coordination and spatial memory. Blocking the expression of the AAV‐ShRNATau, thereby allowing tau levels to return to control levels, restored motor coordination and spatial memory. Mechanistically, the reduced tau levels were associated with lower BDNF levels, reduced levels of synaptic proteins associated with learning, and decreased spine density. We provide compelling evidence that tau is necessary for motor and cognitive function in the adult brain, thereby firmly supporting that tau loss‐of‐function may contribute to the clinical manifestations of many tauopathies. These findings have profound clinical implications given that anti‐tau therapies are in clinical trials for Alzheimer's disease.
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影响因子：
3.3
作者：
Dawson, H. N.;Cantillana, V.;Jansen, M.;Wang, H.;Vitek, M. P.;Wilcock, D. M.;Lynch, J. R.;Laskowitz, D. T.
通讯作者：
Laskowitz, D. T.
影响因子：
4
作者：
Kowiański P;Lietzau G;Czuba E;Waśkow M;Steliga A;Moryś J
通讯作者：
Moryś J
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
4.3
作者：
Khan SS;Bloom GS
通讯作者：
Bloom GS
DOI：
10.1073/pnas.1012851108
发表时间：
2010-12-28
影响因子：
11.1
作者：
Caccamo, Antonella;Maldonado, Monica A.;Oddo, Salvatore
通讯作者：
Oddo, Salvatore