Swedish amyloid precursor protein mutation increases phosphorylation of eIF2α in vitro and in vivo

Kim, Hye‐Sun; Choi, Yoori; Shin, Kwang Yong; Joo, Yeon Ho; Lee, Yong-Kyu; Jung, Sang Yong; Suh, Yoo‐Hun; Kim, Joung-Hun

doi:10.1002/jnr.21267

Cited by 45 publications

(40 citation statements)

References 34 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with previous findings, we found that phosphorylation of eIF2a was significantly increased in the hippocampi of 12-to 16-month-old Tg2576 mice compared to age-matched non-transgenic mice (Figs. 4B,E, P < 0.001 vs. saline treated Tg2576 mice; Kim et al, 2007). Treatment with PBA completely suppressed eIF2a phosphorylation in Tg2576 mice, indicating relief of ER stress ( Fig.…”

Section: Effects Of Pba On Intraneuronal Ab and Er Stress Responsesmentioning

confidence: 86%

“…Decreased Ab accumulation and GRP78 upregulation was associated with a normalization of the levels of phosphorylated eIF2a, an indicator of ER stress which shuts down protein synthesis and is increased in brains of AD animal models and AD patients (Chang et al, 2002;Kim et al, 2007). Altered eIF2a phosphorylation may decrease the efficacy of mRNA translation and de novo protein synthesis which are required for plasticity and normalization of this parameter might contribute to the improvement in learning and memory conferred by PBA.…”

Section: Effects Of Pba On Ab Clearancementioning

confidence: 86%

See 1 more Smart Citation

Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease

et al. 2010

View full text Add to dashboard Cite

Alzheimer's disease (AD) and ageing are associated with impaired learning and memory, and recent findings point toward modulating chromatin remodeling through histone acetylation as a promising therapeutic strategy. Here we report that systemic administration of the HDAC inhibitor 4-phenylbutyrate (PBA) reinstated fear learning in the Tg2576 mouse model of AD. Tg2576 mice develop age-dependent amyloid pathology and cognitive decline that closely mimics disease progression in humans. Memory reinstatement by PBA was observed independently of the disease stage: both in 6-month-old Tg2576 mice, at the onset of the first symptoms, but also in aged, 12- to 16-month-old mice, when amyloid plaque deposition and major synaptic loss has occurred. Reversal of learning deficits was associated to a PBA-induced clearance of intraneuronal Aβ accumulation, which was accompanied by mitigation of endoplasmic reticulum (ER) stress, and to restoration of dendritic spine densities of hippocampal CA1 pyramidal neurons to control levels. Furthermore, the expression of plasticity-related proteins such as the NMDA receptor subunit NR2B and the synaptic scaffold SAP102 was significantly increased by PBA. Our data suggest that the beneficial effects of PBA in memory are mediated both via its chemical chaperone-like activity and via the transcriptional activation of a cluster of proteins required for the induction of synaptic plasticity and structural remodeling.

show abstract

Section: Effects Of Pba On Intraneuronal Ab and Er Stress Responsesmentioning

confidence: 86%

Section: Effects Of Pba On Ab Clearancementioning

confidence: 86%

Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease

et al. 2010

View full text Add to dashboard Cite

show abstract

“…In addition, increased eIF2a phosphoryation in the brain is associated with epilepsy (Carnevalli et al 2006) and neuronal culture models of Parkinson's disease (PD) (Holtz and O'Malley 2003). Moreover, eIF2a phosphorylation increases in the hippocampus of mouse models of Alzheimer's disease (Page et al 2006;Kim et al 2007), as well as brains of AD patients (Kim et al 2007). Mutations in phosphatase and tensin homolog on chromosome ten (PTEN), a tumor suppressor gene involved in upstream regulation of Akt and mTOR signaling, have been reported in autistic individuals with macrocephaly (Butler et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Making synaptic plasticity and memory last: mechanisms of translational regulation

Richter

Klann²

2009

Genes Dev.

316

271

View full text Add to dashboard Cite

Synaptic transmission in neurons is a measure of communication at synapses, the points of contact between axons and dendrites. The magnitude of synaptic transmission is a reflection of the strength of these synaptic connections, which in turn can be altered by the frequency with which the synapses are stimulated, the arrival of stimuli from other neurons in the appropriate temporal window, and by neurotrophic factors and neuromodulators. The ability of synapses to undergo lasting biochemical and morphological changes in response to these types of stimuli and neuromodulators is known as synaptic plasticity, which likely forms the cellular basis for learning and memory, although the relationship between any one form synaptic plasticity and a particular type of memory is unclear. RNA metabolism, particularly translational control at or near the synapse, is one process that controls long-lasting synaptic plasticity and, by extension, several types of memory formation and consolidation. Here, we review recent studies that reflect the importance and challenges of investigating the role of mRNA translation in synaptic plasticity and memory formation.Changes in gene expression are required to convert shortterm memory (STM), lasting less than ;1 h, to long-term memory (LTM) in both invertebrates and vertebrates (Kandel 2001). At the cellular level, long-lasting changes in synaptic strength, typically called synaptic plasticity, refers to the ability of neurons to alter communication with each other via synaptic connections in response to specific patterns of electrical stimulation and/or neurotrophic factors, and is generally considered to underlie LTM (Malenka and Nicoll 1999). The most studied forms of long-lasting synaptic plasticity in mammals, particularly rodents, are long-term potentiation (LTP) and longterm depression (LTD), which refer to long-lasting increases or decreases, respectively, in synaptic strength (Malenka and Bear 2004). Most of the work on LTP and LTD has been conducted in the hippocampus, a structure required for memory consolidation. Similar to memory, LTP can be defined temporally with respect to the requirement for new gene expression: Early-phase LTP (E-LTP), like STM, does not require new gene expression, whereas latephase LTP (L-LTP) does. Throughout the 1990s, molecular studies of the regulation of gene expression in the context of LTM formation and L-LTP focused almost exclusively on transcription, especially the transcription factor CREB (Silva et al. 1998). However, in the last five years, there have been several studies delineating the mechanisms of translational control underlying both LTM and L-LTP.Pharmacological inhibitors of transcription and translation block L-LTP induced by electrical stimulation (Klann and Dever 2004;). Ribosomes, translation factors, and mRNA are present not only in the neuronal soma, but also in dendrites and dendritic spines (Steward and Schuman 2001), suggesting that local (synaptodendritic) protein synthesis could trigger long-lasting synaptic plasticity w...

show abstract

“…A link between Alzheimer’s disease (AD) and reduced global translation was established in 1989, when Langstrom et al demonstrated that polysomes from the cortices of AD patients were associated with less RNA than those from controls. Subsequently, increased levels of p-eIF2α were found in the cortex and hippocampus of AD patients and in AD mouse models (Chang et al, 2002b; Devi and Ohno, 2013; Hoozemans et al, 2009; Kim et al, 2007; Lewerenz and Maher, 2009; Ma et al, 2013; Mouton-Liger et al, 2012; O’Connor et al, 2008; Page et al, 2006; Stutzbach et al, 2013; Unterberger et al, 2006). In addition to AD, p-eIF2α levels are elevated in the brain or spinal cord of patients and mice with prion disease (Unterberger et al, 2006), amyotrophic lateral sclerosis (ALS; Ilieva et al, 2007), Parkinson’s disease (PD; Hoozemans et al, 2007, 2012), Huntington’s disease (HD; Leitman et al, 2014), and various tauopathies (Köhler et al, 2014; Nijholt et al, 2012; Radford et al, 2015; Stutzbach et al, 2013; Unterberger et al, 2006).…”

Section: Neurodegenerative Diseases Associated With Dysregulation Of mentioning

confidence: 99%

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

Kapur

Monaghan

Ackerman

2017

Neuron

180

167

View full text Add to dashboard Cite

SUMMARY Dynamic regulation of mRNA translation initiation and elongation is essential for the survival and function of neural cells. Global reductions in translation initiation resulting from mutations in the translational machinery or inappropriate activation of the integrated stress response may contribute to pathogenesis in a subset of neurodegenerative disorders. Aberrant proteins generated by non-canonical translation initiation may be a factor in the neuron death observed in the nucleotide repeat expansion diseases. Dysfunction of central components of the elongation machinery, such as the tRNAs and their associated enzymes, can cause translation infidelity and ribosome stalling, resulting in neurodegeneration. Taken together, dysregulation of mRNA translation is emerging as a unifying mechanism underlying the pathogenesis of many neurodegenerative disorders.

show abstract

Swedish amyloid precursor protein mutation increases phosphorylation of eIF2α in vitro and in vivo

Cited by 45 publications

References 34 publications

Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease

Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease

Making synaptic plasticity and memory last: mechanisms of translational regulation

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

Contact Info

Product

Resources

About