Alzheimer’s disease-related dysregulation of protein synthesis causes key pathological features with ageing

Abstract

Alzheimer's disease (AD) is characterised by Aβ and tau pathology as well as synaptic degeneration. Recently, it was suggested that the development of these key disease features may at least in part be due to increased protein synthesis that is regulated by fragile X mental retardation protein (FMRP) and its binding partner CYFIP2. Using an unbiased screen, we show that exposure of primary neurons to Aβ increases FMRP-regulated protein synthesis and involves a reduction of CYFIP2 levels. Modelling this CYFIP2 reduction in mice, we find Aβ accumulation, development of pre-tangle tau pathology, gliosis, loss of synapses, and deficits in memory formation with ageing. We conclude that reducing endogenous CYFIP2 expression is sufficient to cause some key features of AD in mice. We therefore propose a central role for CYFIP2 in AD as a modulator of protein synthesis, highlighting a novel direction for therapeutic targeting.

Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases

“…83−85 MINK1 inhibition has been suggested as therapeutically beneficial in AD, as it blocks downstream effects of Aβ accumulation that propagate AD-like pathology in mice. 83 This combination of human-and mousebased data support the development of high-quality chemical inhibitors of MINK1 as AD therapeutics.…”

“…MINK1 was found to be differentially expressed in postmortem AD brains versus healthy controls, and a SNP within MINK1 was strongly correlated with increased risk for AD (Table ). Dysregulation of MINK1 is proposed to result in excessive eukaryotic translation factor 4E and/or tau phosphorylation in the AD brain. − MINK1 inhibition has been suggested as therapeutically beneficial in AD, as it blocks downstream effects of Aβ accumulation that propagate AD-like pathology in mice . This combination of human- and mouse-based data support the development of high-quality chemical inhibitors of MINK1 as AD therapeutics.…”

A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice

“…Additional tests are needed to determine if the approach is viable in additional animal and patient models. Aberrant translation is a dominant theme in neurobiology beyond FXS and has been reported in Alzheimer's, ALS, and vanishing white matter disease [101][102][103]. The identification of a highly specific inhibitor that can access the CNS provides a powerful new tool for attenuating dysregulated cap-dependent translation in the brain.…”