Casein Kinase 2 dependent phosphorylation of eIF4B regulates BACE1 expression in Alzheimer\u2019s disease

Barbara Bettegazzi,Fabio Grohovaz,Alessio Vittorio Colombo,Serena Bellani,Daniele Zacchetti,Nikolaus Deigendesch,Franca Codazzi,Takaomi C Saido,Lisa Michelle Restelli,Stephan Frank,Sabina Tahirovic,Laura Sebastian Monasor,Takashi Saito,Sven Lammich

doi:10.1038/s41419-021-04062-3

Abstract

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Increased Aβ production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aβ generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.

Highlights

Alzheimer’s disease (AD), the most common form of dementia, imposes a very high social burden, which has been steadily increasing in the last twenty years
Particular attention has been devoted to BACE1, the enzyme that controls amyloid-β peptide (Aβ) production by cleaving the amyloid-β precursor protein (APP), and whose dysregulation has been reported in AD patients [10,11,12,13]
There is consensus that the presence of a highly structured and The knockdown of eIF4B (Fig. 2F–I, J–L) was able to prevent upstream AUG endowed 5′UTR determines an inhibition of the reduction in full-length APP levels promoted by bicuculline

Summary

Introduction

Alzheimer’s disease (AD), the most common form of dementia, imposes a very high social burden, which has been steadily increasing in the last twenty years. A precise definition of the link between synaptic activity and BACE1 modulation is still needed, even more so after the observation that AD patients treated with BACE1 inhibitors showed a modest worsening of cognitive performance [18,19,20]. In this respect, the elucidation of the mechanisms controlling BACE1 expression may offer further insights into our understanding of the disease and in the development of therapeutic approaches

Methods

Results

Conclusion