Abstract

Alzheimers disease (AD) is characterised by A{beta} 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 A{beta} increases FMRP-regulated protein synthesis and involves a reduction of CYFIP2 levels. Modelling this CYFIP2 reduction in mice, we find A{beta} 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.