King's College London

Amyloid-β (Aβ) ‘plaques’ and phosphorylated tau ‘tangles’ are pathological hallmarks of Alzheimer’s disease (AD), the most common form of dementia in adults. However, synaptic degeneration occurs early in AD, making its understanding critical for the development of treatments. Synaptic function requires rapid access to specific macromolecules, and several proteins can be locally synthesised within dendrites or spines. Such localisation of protein synthesis is regulated by RNA-binding proteins and associated molecules, such as Cytoplasmic FMRP-Interacting Protein 2 (CYFIP2), which was previously found to be reduced in the AD brain. CYFIP2 has been proposed to regulate protein translation via its ability to interact with the eukaryotic initiation factor 4E (eIF4E), including at synapses. The first aim of this work was to decipher how CYFIP2 may be lost in AD. Using an in vitro model of AD, it was found that Aβ may be the primary cause of CYFIP2 reduction, leading to its proteasomal degradation. Mechanistically, Aβ results in eIF4E phosphorylation, enabling its dissociation from CYFIP2 while increasing protein translation. The second aim was to comprehend the impact of CYFIP2 reduction in the intact mouse brain, using Cyfip2+/- mice as a model of reduced CYFIP2 expression. Biochemical analyses indicated that CYFIP2 can post-transcriptionally regulate protein levels of a subset of FMRP-bound mRNAs, specifically in synapses. This was associated with increased Aβ 1-42 levels and site-specific tau phosphorylation. The final aim was to determine whether ageing, the biggest risk factor for AD, might exacerbate these conditions. Cyfip2+/- mice showed startling development of tau pathology at 12 months of age. This included dendritic accumulation of pathologically phosphorylated tau accompanied by gliosis, as well as the presence of pre-tangle-like structures, which were absent in wild-type littermates. These studies suggest that simply reducing CYFIP2 expression in mice can model some key features of AD. Therefore, this body of work proposes a central role for CYFIP2 in AD, as a potential modulator of synaptic protein translation. By identifying novel signalling processes underlying Aβ and tau pathology, this research substantiates innovative approaches to AD therapeutics.