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

Benoit Souchet (1, 2) , Mickael Audrain (1) , Jean Marie Billard (3, 4) , Julien Dairou (5) , Romain Fol (1) , Nicola Salvatore Orefice (1) , Satoru Tada (1) , Yuchen Gu (3, 2) , Gaelle Dufayet-Chaffaud (1) , Emmanuelle Limanton (6) , François Carreaux (6) , Jean-Pierre Bazureau (6) , Sandro Alves (1) , Laurent Meijer (7) , Nathalie Janel (2) , Jérome Braudeau (1) , Nathalie Cartier (1)

1 U 1169 - Thérapie génique, Génomique et Epigénomique
2 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
3 U894 / UMS 1266 - Institut de psychiatrie et neurosciences
4 COMETE - Mobilités : Vieillissement, Pathologie, Santé
5 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
6 ISCR - Institut des Sciences Chimiques de Rennes
7 ManRos Therapeutics

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.

Keywords: Kinase specificity; Therapeutic approach; Alzheimer's disease; DYRK1A; Proteolysis

Domains: Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]

Benoit Souchet, Mickael Audrain, Jean Marie Billard, Julien Dairou, Romain Fol, et al.. Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice. Acta Neuropathologica Communications, 2019, 7 (1), pp.46. ⟨10.1186/s40478-019-0678-6⟩. ⟨hal-02324924⟩