title: Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss.
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-β42Reduced 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.
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Sachin Suresh
authors.initials: SS
authors.lastname: Tiwari
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Keiko
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Anshua
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Wajeeha
authors.initials: W
authors.lastname: Aziz
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Daoud
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Vidushi
authors.initials: V
authors.lastname: Golash
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK 2 Department of Neuropathology, Institute of Pathology, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.affiliation: 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK karl.giese@kcl.ac.uk.
authors.forename: Karl Peter
authors.initials: KP
authors.lastname: Giese
keywords: BACE1; amyloid beta; mRNA translation; spatial memory; tau phosphorylation