Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
Alzheimer's Disease Center, Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Sci Transl Med. 2022 Apr 27;14(642):eabm5527. doi: 10.1126/scitranslmed.abm5527.
Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally.
TAU 聚集体的细胞内积累是几种神经退行性疾病的标志。然而，在缺乏这种 TAU 病理学的其他脑部疾病模型中，TAU 的全局遗传减少也是有益的，这表明非聚集 TAU 具有致病性。在这里，条件性敲除兴奋性神经元而非抑制性神经元中的 TAU 可减少癫痫、癫痫猝死、磷酸肌醇 3-激酶-AKT-雷帕霉素靶蛋白通路的过度激活、脑过度生长（巨脑症）和 Dravet 综合征小鼠模型中的自闭症样行为，Dravet 综合征是一种儿童早期严重的癫痫性脑病。此外，在该小鼠模型中，于出生后第 10 天开始用降低 TAU 的反义寡核苷酸进行治疗具有类似的治疗效果。我们的研究结果表明，兴奋性神经元是 TAU 必须减少以对抗与 Dravet 综合征相关的脑功能障碍的关键细胞类型，并且即使在出生后开始进行整体大脑 TAU 减少也可能具有相似的益处。
