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Journal articles
Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice
Abstract : Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer's disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. These findings were confirmed in APP/ PS1 mice, an amyloid model of AD, suggesting that this DYRK1A cleavage is a consequence of the amyloid pathology. We identified in vitro the Leucettine L41 as a compound able to prevent DYRK1A proteolysis in both human and mouse protein extracts. We then showed that intraperitoneal injections of L41 in aged APP/PS1 mice inhibit STAT3ɑ phosphorylation and reduce pro-inflammatory cytokines levels (IL1-β, TNF-ɑ and IL-12) associated to an increased microglial recruitment around amyloid plaques and decreased amyloid-β plaque burden. Importantly, L41 treatment improved synaptic plasticity and rescued memory functions in APP/PS1 mice. Collectively, our results suggest that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Further evaluation of inhibitors of DYRK1A truncation promises a new therapeutic approach for AD.
Cited literature [49 references]
https://hal-normandie-univ.archives-ouvertes.fr/hal-02324924
Contributor : Jean-Marie Billard <>
Submitted on : Thursday, October 24, 2019 - 2:11:28 PM
Last modification on : Tuesday, January 12, 2021 - 4:37:55 PM
Long-term archiving on: : Saturday, January 25, 2020 - 3:52:38 PM
Contributor : Jean-Marie Billard <>
Submitted on : Thursday, October 24, 2019 - 2:11:28 PM
Last modification on : Tuesday, January 12, 2021 - 4:37:55 PM
Long-term archiving on: : Saturday, January 25, 2020 - 3:52:38 PM
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