Abnormal tau induces cognitive impairment through two different mechanisms: synaptic dysfunction and neuronal loss

被引:100
作者
Di, J. [1 ,2 ,4 ]
Cohen, L. S. [1 ,2 ]
Corbo, C. P. [3 ]
Phillips, G. R. [1 ,2 ]
El Idrissi, A. [1 ,2 ]
Alonso, A. D. [1 ,2 ]
机构
[1] CUNY Coll Staten Isl, Dept Biol, Staten Isl, NY 10314 USA
[2] CUNY Coll Staten Isl, Ctr Dev Neurosci, Staten Isl, NY 10314 USA
[3] Wagner Coll, Dept Biol Sci, Staten Isl, NY 10301 USA
[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
关键词
ALZHEIMERS-DISEASE; TRANSGENIC MOUSE; DOWN-SYNDROME; NEUROFIBRILLARY TANGLES; FUNCTIONAL-LINK; PHOSPHORYLATION; MEMORY; MICE; PROTEIN; AGGREGATION;
D O I
10.1038/srep20833
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
The hyperphosphorylated microtubule-associated protein tau is present in several neurodegenerative diseases, although the causal relationship remains elusive. Few mouse models used to study Alzheimer-like dementia target tau phosphorylation. We created an inducible pseudophosphorylated tau (Pathological Human Tau, PH-Tau) mouse model to study the effect of conformationally modified tau in vivo. Leaky expression resulted in two levels of PH-Tau: low basal level and higher upon induction (4% and 14% of the endogenous tau, respectively). Unexpectedly, low PH-Tau resulted in significant cognitive deficits, decrease in the number of synapses (seen by EM in the CA1 region), reduction of synaptic proteins, and localization to the nucleus. Induction of PH-Tau triggered neuronal death (60% in CA3), astrocytosis, and loss of the processes in CA1. These findings suggest, that phosphorylated tau is sufficient to induce neurodegeneration and that two different mechanisms can induce cognitive impairment depending on the levels of PH-Tau expression.
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页数:12
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