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Springer Science and Business Media LLC Molecular Brain 16(1)
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    초록·키워드

    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 (STEP<sub>61</sub>). Whereas the role of Fyn has been widely explored, less is known about STEP<sub>61</sub> 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 STEP<sub>61</sub> and its activity in human and animal brain tissue and observed a correlation between STEP<sub>61</sub> and disease progression. In early-stage human AD, an initial increase in the level and activity of STEP<sub>61</sub> was observed, which decreased with the loss of the synaptic marker PSD-95; in FTD-tau, there was a reduction in STEP<sub>61</sub> and PSD-95 which correlated with clinical diagnosis. In APP23 mice with an amyloid-β pathology, the level and activity of STEP<sub>61</sub> 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 STEP<sub>61</sub> 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.

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