A γ-adducin cleavage fragment induces neurite deficits and synaptic dysfunction in Alzheimer's disease.

Min Xiong, Li Zou, Lanxia Meng, Xingyu Zhang, Ye Tian, Guoxin Zhang, Jiaolong Yang, Guiqin Chen, Jing Xiong, Keqiang Ye, Zhentao Zhang

Progress in neurobiology 2021 Aug

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Neurite deficits and synaptic dysfunction contribute to cognitive impairments in Alzheimer's disease (AD). However, the underlying molecular mechanisms remain unclear. Here, we show that γ-adducin, a cytoskeleton-associated protein that assembles the spectrin-actin framework, is cleaved by a lysosomal cysteine proteinase named asparagine endopeptidase (AEP). AEP is upregulated and activated during aging and cleaves γ-adducin at N357, disrupting spectrin-actin assembly. Moreover, γ-adducin (1-357) fragment downregulates the expression of Rac2, leading to defects in neurite outgrowth. Expression of the γ-adducin (1-357) fragment in the hippocampus of tau P301S transgenic mice resulted in significant AD-like pathology and cognitive deficits. In summary, AEP-mediated fragmentation of γ-adducin plays a vital role in AD. Blocking the activity of AEP might be a novel therapeutic target for AD. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Min Xiong, Li Zou, Lanxia Meng, Xingyu Zhang, Ye Tian, Guoxin Zhang, Jiaolong Yang, Guiqin Chen, Jing Xiong, Keqiang Ye, Zhentao Zhang. A γ-adducin cleavage fragment induces neurite deficits and synaptic dysfunction in Alzheimer's disease. Progress in neurobiology. 2021 Aug;203:102074