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

Tiwari, Sachin S.; Mizuno, Keiko; Ghosh, Anshua; Aziz, Wajeeha; Troakes, Claire; Daoud, Jason; Golash, Vidushi; Noble, Wendy; Hortobágyi, Tibor; Giese, K. Peter

doi:10.1093/brain/aww205

Cited by 56 publications

(84 citation statements)

References 60 publications

(108 reference statements)

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“…Given that CYFIP2 is downregulated in post-mortem AD brain 22 , in a mouse model of AD 22 , and in primary cortical neurons following treatment with Aβ1-42 oligomers (Fig. 2i, j), we speculated that its reduction may be important in the pathogenesis of AD.…”

Section: Cyfip2 Reduction Leads To Age-dependent Accumulation Of Pre-mentioning

confidence: 99%

“…Previously, we reported that 3-4 month old heterozygous Cyfip2 null mutants (Cyfip2 +/-), having about 50% reduced CYFIP2 expression, have increased levels of tau phosphorylation at Ser214, possibly due to a post-transcriptional increase in αCaMKII levels 22 . Here, we also found increased tau phosphorylation at Ser416, a αCaMKIIspecific phospho-site 40,41 , when normalised to levels of total tau ( Supplementary Fig.…”

Section: Cyfip2 Reduction Leads To Age-dependent Accumulation Of Pre-mentioning

confidence: 99%

“…In addition to regulating translation of mRNA, CYFIP1 and CYFIP2 are part of the Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein (WAVE) complex that regulates actin polymerisation at synapses 24,25 . CYFIP2 protein expression is reduced in post-mortem AD brain and in an AD mouse model 22 . Modelling the AD-related reduced CYFIP2 expression in heterozygous Cyfip2 null mutant mice (Cyfip2 +/-), which have no overt phenotypes 18 , led to increased APP protein expression, enhanced tau phosphorylation at CaMKII phospho-sites in synapses, elevated soluble Aβ1-42 levels, and changes in synapse morphology in the young adult hippocampus 22 .…”

Section: Introductionmentioning

confidence: 99%

“…CYFIP2 protein expression is reduced in post-mortem AD brain and in an AD mouse model 22 . Modelling the AD-related reduced CYFIP2 expression in heterozygous Cyfip2 null mutant mice (Cyfip2 +/-), which have no overt phenotypes 18 , led to increased APP protein expression, enhanced tau phosphorylation at CaMKII phospho-sites in synapses, elevated soluble Aβ1-42 levels, and changes in synapse morphology in the young adult hippocampus 22 .…”

Section: Introductionmentioning

confidence: 99%

“…Both proteins are expressed in various tissues including the brain 18 , where they localise to both excitatory 19 and inhibitory 20 synapses of hippocampal neurons. Although little is known about their precise function due to their relatively recent discovery, they have both overlapping and unique functions 21,22 . CYFIP1 is thought to repress cap-dependent translation of specific mRNAs by interacting with the eukaryotic initiation factor 4E (eIF4E), and CYFIP2 has an identical eIF4E-binding motif to CYFIP1 21,23 .…”

Section: Introductionmentioning

confidence: 99%

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

Ghosh

Mizuno

Tiwari

et al. 2019

Preprint

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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.

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Section: Cyfip2 Reduction Leads To Age-dependent Accumulation Of Pre-mentioning

confidence: 99%

Section: Cyfip2 Reduction Leads To Age-dependent Accumulation Of Pre-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Ghosh

Mizuno

Tiwari

et al. 2019

Preprint

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De novo hotspot variants in CYFIP2 cause early‐onset epileptic encephalopathy

Nakashima

Kato

Aoto

et al. 2018

Annals of Neurology

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Majority of cerebrospinal fluid‐contacting neurons in the spinal cord of C57Bl/6N mice is present in ectopic position unlike in other studied experimental mice strains and mammalian species

Gombalová

Košuth

Matiašová

et al. 2020

J of Comparative Neurology

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Cerebrospinal fluid contacting neurons (CSF‐cNs) represent a specific class of neurons located in close vicinity of brain ventricles and central canal. In contrast with knowledge gained from other vertebrate species, we found that vast majority of CSF‐cNs in the spinal cord of C57Bl/6N mice is located in ectopic distal ventral position. However, we found that small number of ectopic CSF‐cNs is present also in spinal cord of other investigated experimental mice strains (C57Bl/6J, Balb/C) and mammalian species (Wistar rats, New Zealand White rabbits). Similarly, as the proximal populations, ectopic CSF‐cNs retain PKD2L1‐immunoreactivity and synaptic contacts with other neurons. On the other side, they show rather multipolar morphology lacking thick dendrite contacting central canal lumen. Ectopic CSF‐cNs in the spinal cord of C57Bl/6N mice emerge during whole period devoted to production of CSF‐cNs and reach their ventral destinations during first postnatal weeks. In order to identify major gene, whose impairment could trigger translocation of CSF‐cNs outside the central canal area, we took advantage of close consanguinity of C57Bl/6J substrain with normal CSF‐cN distribution and C57Bl/6N substrain with majority of CSF‐cNs in ectopic position. Employing in silico analyses, we ranked polymorphisms in C57Bl/6N substrain and selected genes Crb1, Cyfip2, Adamts12, Plk1, and Herpud2 as the most probable candidates, whose product dysfunction might be responsible for the ectopic distribution of CSF‐cNs. Furthermore, segregation analysis of F2 progeny of parental C57Bl/6N and Balb/C mice revealed that polymorphic loci of Crb1 and Cyfip2 underlie the ectopic position of CSF‐cNs in the spinal cord of C57Bl/6N mice.

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

Cited by 56 publications

References 60 publications

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

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

De novo hotspot variants in CYFIP2 cause early‐onset epileptic encephalopathy

Majority of cerebrospinal fluid‐contacting neurons in the spinal cord of C57Bl/6N mice is present in ectopic position unlike in other studied experimental mice strains and mammalian species

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