Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss.

Sachin Suresh Tiwari,Wendy Noble,Claire Troakes,Wajeeha Aziz,Vidushi Golash,Tibor Hortobágyi,Tibor Hortobágyi,Anshua Ghosh,Jason Daoud,Keiko Mizuno,Karl Peter Giese

doi:10.1093/brain/aww205

Abstract

Characteristic features of Alzheimer's disease are memory loss, plaques resulting from abnormal processing of amyloid precursor protein (APP), and presence of neurofibrillary tangles and dystrophic neurites containing hyperphosphorylated tau. Currently, it is not known what links these abnormalities together. Cytoplasmic FMR1 interacting protein 2 (CYFIP2) has been suggested to regulate mRNA translation at synapses and this may include local synthesis of APP and alpha-calcium/calmodulin-dependent kinase II, a kinase that can phosphorylate tau. Further, CYFIP2 is part of the Wiskott-Aldrich syndrome protein-family verprolin-homologous protein complex, which has been implicated in actin polymerization at synapses, a process thought to be required for memory formation. Our previous studies on p25 dysregulation put forward the hypothesis that CYFIP2 expression is reduced in Alzheimer's disease and that this contributes to memory impairment, abnormal APP processing and tau hyperphosphorylation. Here, we tested this hypothesis. First, in post-mortem tissue CYFIP2 expression was reduced by ∼50% in severe Alzheimer's hippocampus and superior temporal gyrus when normalized to expression of a neuronal or synaptic marker protein. Interestingly, there was also a trend for decreased expression in mild Alzheimer's disease hippocampus. Second, CYFIP2 expression was reduced in old but not in young Tg2576 mice, a model of familial Alzheimer's disease. Finally, we tested the direct impact of reduced CYFIP2 expression in heterozygous null mutant mice. We found that in hippocampus this reduced expression causes an increase in APP and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) protein, but not mRNA expression, and elevates production of amyloid-β42 Reduced CYFIP2 expression also increases alpha-calcium/calmodulin-dependent kinase II protein expression, and this is associated with hyperphosphorylation of tau at serine-214. The reduced expression also impairs spine maturity without affecting spine density in apical dendrites of CA1 pyramidal neurons. Furthermore, the reduced expression prevents retention of spatial memory in the water maze. Taken together, our findings indicate that reduced CYFIP2 expression triggers a cascade of change towards Alzheimer's disease, including amyloid production, tau hyperphosphorylation and memory loss. We therefore suggest that CYFIP2 could be a potential hub for targeting treatment of the disease.

Highlights

Alzheimer’s disease is a neurodegenerative disease that causes memory loss
This effect was modelled in mice and we found that reduced CYFIP2 expression leads to increased amyloid precursor protein (APP), b-site APP cleaving enzyme 1 (BACE1), and aCaMKII protein expression, abnormal amyloid-b42 production, tau hyperphosphorylation at serine-214, alterations in dendritic spine morphology, and memory loss
We found that CYFIP2/ synaptophysin expression was significantly decreased by $40% in severe Alzheimer’s disease hippocampus (t = 2.43; P 5 0.05; Supplementary Fig. 3), suggesting that CYFIP2 expression declines before synapse loss occurs

Summary

Introduction

Alzheimer’s disease is a neurodegenerative disease that causes memory loss. The pathological hallmarks of Alzheimer’s disease are the occurrence of amyloid plaques and neurofibrillary tangles, next to substantial neuronal loss in forebrain (Braak and Braak, 1991; Hardy and Selkoe, 2002). Post-mortem brain analyses have established that synapse loss precedes neuronal loss in Alzheimer’s disease (Arendt, 2009). This synaptic degeneration correlates best with the memory impairment (deKosky and Scheff, 1990; Terry et al, 1991; Coleman et al, 2004). FMRP binds to cytoplasmic FMRP-interacting proteins 1 and 2 (CYFIP1 and CYFIP2) (Schenck et al, 2001). Both of these proteins are expressed at synapses of hippocampal neurons (Pathania et al, 2014). In addition to regulating translation of mRNA, CYFIP1 and CYFIP2 are part of the Wiskott-Aldrich syndrome proteinfamily verprolin-homologous protein (WAVE) complex that regulates actin polymerization at synapses (Eden et al, 2002; De Rubeis et al, 2013)

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