Tyrosine phosphatase STEP61 in human dementia and in animal models with amyloid and tau pathology

Molecular Brain

Micro Report

Deonne Taylor¹  Andrew Kneynsberg¹  Jürgen Götz¹  Marloes van Roijen² 

[1] Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St. Lucia Campus, Brisbane, QLD, Australia;New South Wales Brain Bank, The University of Sydney, Sydney, NSW, Australia;

关键词: Alzheimer’s disease;    Amyloid-β;    Frontotemporal dementia;    Striatal-enriched tyrosine phosphatase 61 (STEP);    Microtubule-associated protein tau;    Transgenic mice;   

DOI  :  10.1186/s13041-023-00994-3

 received in 2021-09-28, accepted in 2022-12-30,  发布年份 2022

来源: Springer

【 摘 要 】

Synaptic degeneration is a precursor of synaptic and neuronal loss in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia with tau pathology (FTD-tau), a group of primary tauopathies. A critical role in this degenerative process is assumed by enzymes such as the kinase Fyn and its counterpart, the phosphatase striatal-enriched tyrosine phosphatase 61 (STEP61). Whereas the role of Fyn has been widely explored, less is known about STEP61 that localises to the postsynaptic density (PSD) of glutamatergic neurons. In dementias, synaptic loss is associated with an increased burden of pathological aggregates. Tau pathology is a hallmark of both AD (together with amyloid-β deposition) and FTD-tau. Here, we examined STEP61 and its activity in human and animal brain tissue and observed a correlation between STEP61 and disease progression. In early-stage human AD, an initial increase in the level and activity of STEP61 was observed, which decreased with the loss of the synaptic marker PSD-95; in FTD-tau, there was a reduction in STEP61 and PSD-95 which correlated with clinical diagnosis. In APP23 mice with an amyloid-β pathology, the level and activity of STEP61 were increased in the synaptic fraction compared to wild-type littermates. Similarly, in the K3 mouse model of FTD-tau, which we assessed at two ages compared to wild-type, expression and activity of STEP61 were increased with ageing. Together, these findings suggest that STEP contributes differently to the pathogenic process in AD and FTD-tau, and that its activation may be an early response to a degenerative process.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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Fig. 1