Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice

Benoît SouchetEmail author View ORCID ID profile,
Mickael Audrain,
Jean Marie Billard,
Julien Dairou,
Romain Fol,
Nicola Salvatore Orefice,
Satoru Tada,
Yuchen Gu,
Gaelle Dufayet-Chaffaud,
Emmanuelle Limanton,
François Carreaux,
Jean-Pierre Bazureau,
Sandro Alves,
Laurent Meijer,
Nathalie Janel,
Jérôme Braudeau†Email author and
Nathalie Cartier†Email author

†Contributed equally

Acta Neuropathologica Communications20197:46

https://doi.org/10.1186/s40478-019-0678-6

Received: 4 January 2019
Accepted: 14 February 2019
Published: 18 March 2019

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.