PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Neurobiol Aging. Author manuscript; available in PMC 2017 May 1.
Published in final edited form as:
PMCID: PMC4841914
NIHMSID: NIHMS766812

Repression of the eIF2α kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer’s disease

Abstract

Mounting evidence indicates that impairments of synaptic efficacy/plasticity may be a key step in the development of Alzheimer’s disease (AD) pathophysiology. Among the two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), much less is known about how LTD is regulated in AD and its molecular mechanisms. Recent studies indicate that metabotropic glutamate receptor 5 (mGluR5) may function as a receptor/co-receptor for Amyloid beta (Aβ). Herein we examined mGluR-LTD in hippocampal slices from aged APP/PS1 mutant mice that model AD. Our findings demonstrate that mGluR-LTD is blocked in APP/PS1 mice, and that the mGluR-LTD failure is reversed by either genetically or pharmacologically suppressing the activity of PERK, a kinase for the mRNA translation factor eIF2α. These data are congruent with recent evidence that inhibition of eIF2α phosphorylation via PERK suppression and reversal of de novo protein synthesis deficits can mitigate cognitive deficits in neurodegenerative diseases. Together with reports indicating that mGluR5 may mediate Aβ synaptotoxicity, our findings offer insights into novel therapeutic targets for AD and other cognitive syndromes.

Keywords: Alzheimer’s disease, mGluR-LTD, PERK, eIF2α, protein synthesis, synaptic plasticity

1. Introduction

Abundant evidence indicates that synaptic dysfunction that results in compromised synaptic efficacy/plasticity (the ability of synapses to strengthen or weaken over time) may be a key step during the development of Alzheimer’s disease (AD) pathophysiology (Selkoe, 2002, Oddo et al., 2003, Jacobsen et al., 2006, Ma et al., 2010, Tomiyama et al., 2010, Ma and Klann, 2012). Thus, understanding the molecular signaling mechanisms underlying these synaptic impairments could yield insights into therapeutic targets for AD. Long-term potentiation (LTP) and long-term depression (LTD) are the intensely studied forms of synaptic plasticity, that work in concert to mediate learning and memory as well as several other forms of experience-dependent changes in brain function (Malenka and Bear, 2004). LTP has been extensively studied in AD, either in the context of exogenous application of soluble beta-amyloid (Aβ), abnormal accumulation of which represents a brain pathology hallmark for AD, or in various transgenic mouse models of AD (Walsh et al., 2002, Rowan et al., 2005, Li et al., 2011, Ma and Klann, 2012). In contrast, very few studies have examined how the molecular mechanisms of LTD are altered in AD models. Moreover, to our knowledge, most of the previous LTD studies in AD have been conducted either in the context of acute exogenous Aβ application or relatively young (less than one year old), but not aged, transgenic mouse models of AD (Kim et al., 2001, Wang et al., 2002, Raymond et al., 2003, Li et al., 2009, D’Amelio et al., 2011, Ma et al., 2012, Megill et al., 2015).

There are two well studied, mechanistically distinct forms of LTD: N-methyl-D-aspartate receptor (NMDAR)-dependent LTD and metabotropic glutamate receptor (mGluR)-dependent LTD. NMDAR-dependent LTD is usually induced by electrical low frequency stimulation (LFS) and requires activation of NMDARs, whereas mGluR-dependent LTD requires activation of group 1 mGluRs (includes mGluR1 and 5) and is often induced by DHPG [(RS)-3,5-dihydroxyphenylglycine], a selective agonist for group 1 mGluRs (Malenka and Bear, 2004, Lüscher and Huber, 2010). Of interest, recent studies indicate that mGluR5 may function as a receptor/co-receptor for Aβ, and an mGluR5 antagonist rescued cognitive defects in AD model mice (Um et al., 2013, Hu et al., 2014). However, the downstream signaling mechanisms mediating the above effects remain unclear.

Long-lasting forms of both LTP and LTD depend on intact mechanisms of de novo protein synthesis (Klann and Dever, 2004, Costa-Mattioli et al., 2009, Richter and Klann, 2009, Rosenberg et al., 2014). Protein synthesis is a highly regulated process, particularly at the initiation phase, and involves various translational factors including eukaryotic initiation factor 2 (eIF2), which plays a key role in synaptic plasticity and memory formation (Klann et al., 2004, Costa-Mattioli et al., 2007, Trinh and Klann, 2013). It is generally considered that in response to specific cellular stress, one (or more) of the four eIF2 kinases -- PKR, HRI, GCN2, or PERK, is activated to phosphorylate eIF2 on the α subunit, leading to inhibition of general protein synthesis and potentially memory impairments if the decreases in protein synthesis are long-lasting (Wek et al., 2006, Wek and Cavener, 2007, Trinh and Klann, 2013, Ma and Klann, 2014). Notably, recent studies have suggested a link between neurodegenerative diseases, including prion disease and AD, and disruption of translational homeostasis due to abnormal PERK/eIF2α signaling. In particular, hyper-phosphorylation of eIF2α via PERK activation is associated with AD and prion disease, and repression of PERK activity rescues cognitive deficits in mouse models of AD, prion disease, and frontotemporal dementia (Moreno et al., 2012, Ma et al., 2013, Moreno et al., 2013, Ma and Klann, 2014, Radford et al., 2015).

Herein, we studied mGluR-LTD at CA3-CA1 synapses in hippocampal slices from aged APP/PS1 AD model mice. Our findings demonstrate that mGluR-LTD is blocked in AD mice, and importantly, the mGluR-LTD blockade is reversed by either genetically or pharmacologically suppressing activity of eIF2α kinase PERK. These data are congruent with evidence that inhibition of eIF2α phosphorylation via PERK suppression and consequently improved de novo protein synthesis can mitigate cognitive deficits in neurodegenerative diseases (Ma and Klann, 2014). Together with reports indicating that mGluR5 may mediate synaptotoxicity of Aβ (Um et al., 2013, Hu et al., 2014), our findings offer insights into novel therapeutic targets for AD and other cognitive syndromes.

2. Materials & Methods

2.1. Mice

All mice were housed in a barrier facility dedicated to transgenic mice at Wake Forest University School of Medicine. The facility operates in accordance with standards and policies of the US Department of Agriculture’s Animal Welfare Information Center (AWIC), and the NIH Guide for Care and Use of Laboratory Animals. The facility is kept on a 12 h light/dark cycle, with a regular feeding and cage-cleaning schedule. Mice of either sex were used. APP/PS1 transgenic mice (APPswe + PSEN1/ΔE9) were purchased from the Jackson Laboratory (Jankowsky et al., 2001). PERK forebrain conditional knockout mice (PERK cKO) were generated as described previously (Trinh et al., 2012). Creation of APP/PS1/PERK cKO double mutant mice was done as described previously (Ma et al., 2013). All genotypes were verified by polymerase chain reaction (PCR). Mice were used at the age of 12–15 months, except for the exogenous Aβ application experiments, for which wild type mice were used at the age of 3–6 months.

2.2. Hippocampal slices preparation and electrophysiology

Hippocampal slices were prepared as described previously (Ma et al., 2011). For electrophysiology experiments, slices were transferred to recording chambers (preheated to 32 °C) where they were superfused with oxygenated ACSF. Monophasic, constant-current stimuli (100 μsec) were delivered with a concentric bipolar microelectrode (FHC Inc., Bowdoin, ME) placed in the stratum radiatum of area CA3, and the field excitatory postsynaptic potentials (fEPSPs) were recorded in the stratum radiatum of area CA1. fEPSPs were acquired, and amplitudes and maximum initial slopes measured, using pClamp 10 (Axon Instruments, Foster City, CA). To induce mGluR-LTD, slices were perfused with DHPG (100 μM in ACSF) for 10 min.

2.3. Drug treatment

DHPG (Abcam, Cambridge, MA) was prepared as stock solution in distilled water and was diluted into a final concentration 100 μM immediately preceding the experiments. Only DHPG stock prepared within one week was used in the experiments. PERK inhibitor I (GSK2606414, Calbiochem/Millipore) was prepared as stock solution in DMSO and was diluted to its final concentration of 1 μM before conducting experiments. Aβ(1–42) stock (100 μM, Bachem) was prepared as described previously (Ma et al., 2010).

2.4. Western blot

As previously described (Ma et al., 2013), mouse hippocampal slices were flash-frozen on dry ice after drug treatment, followed by standard procedure for Western blot. All primary and secondary antibodies were diluted in blocking buffer. Blots were probed with primary antibodies for phospho-eIF2α (1:1000; Cell Signaling), eIF2α (1:1000; Cell Signaling), PERK (1:1000; Santa Cruz), and GAPDH (1:10,000, Cell Signaling). Protein bands were visualized using chemiluminescence (Clarity ECL; Biorad) and the Biorad ChemiDoc MP Imaging System. Densitometric analysis was performed using ImageJ.

2.5. Data analysis

Data are presented as mean ± SEM. Summary data are presented as group means with standard error bars. For comparison between two groups, a two-tailed independent Student’s t-test was used. For comparisons between multiple groups, ANOVA was used followed by individual post hoc tests when applicable. Error probabilities of p < 0.05 were considered statistically significant.

3. Results

3.1. Hippocampal mGluR-LTD is impaired in APP/PS1 mice but unaltered with application of exogenous Aβ

We first asked whether mGluR-LTD was altered in AD model mice by using APP/PS1 mutant mice, a well-established AD model (Jankowsky et al., 2001). mGluR-LTD was induced at CA3-CA1 synapses (Schaffer collateral pathway) in hippocampal slices with application of group 1 mGluR agonist DHPG (100 μM for 10 minutes). For slices derived from wild type (WT) mice, DHPG incubation reliably induced LTD lasting over 1 hour (Fig. 1A–C). In comparison, DHPG induced only transient LTD in slices from APP/PS1 mice (Fig. 1A–C).

Fig. 1
Hippocampal mGluR-LTD is impaired in APP/PS1 mice. (A) DHPG-induced mGluR-LTD was inhibited in slices from APP/PS1 mice (filled circles), compared to WT mice (open squares). (B) Representative fEPSP traces before and after DHPG treatment to induce mGluR-LTD ...

Previous studies demonstrated that exogenous Aβ application results in enhancement of NMDAR-dependent LTD (Li et al., 2009, Ma et al., 2012). To examine the effects of Aβ on mGluR LTD, we applied DHPG to hippocampal slices pre-treated with Aβ (1–42) (Aβ, 500 nM). To our surprise, we found no significant difference in mGluR-LTD between slices treated with vehicle (Fig. 1D–F) and Aβ (Fig. 1D–F). Taken together, these findings indicate that mGluR-LTD is blocked in the aged, chronic AD model mice.

3.2. Conditional PERK gene deletion reverses mGluR-LTD failure in APP/PS1 mice

mGluR-LTD requires de novo protein synthesis (Huber et al., 2000, Hou et al., 2006). In addition, it was demonstrated recently that abnormal hyperphosphorylation of eIF2α due to elevated PERK activity resulted in decreased de novo protein synthesis in the hippocampus of AD model mice (Ma et al., 2013). Therefore we investigated whether mGluR-LTD failure in APP/PS1 mice could be alleviated by restoring translational homeostasis via the genetic suppression of PERK. We bred mice harboring a floxed PERK gene with mice expressing a brain-specific Cre recombinase to generate mice in which PERK was conditionally removed in excitatory neurons in the forebrain late in development (PERK cKO). We further generated a mutant mouse line that expressed both APPswe/PS1ΔE9 and homozygous Cre PERK−/− flox transgenes (APP/PS1/PERK cKO), in which both eIF2α hyperphosphorylation and de novo protein synthesis defects in AD mice were corrected (Ma et al., 2013). We found that hippocampal mGluR-LTD was not altered significantly in PERK cKO mice (Fig.1G–I), compared to WT control mice (Fig.1G–I). Notably, in slices from APP/PS1/PERK cKO mutant mice, DHPG successfully induced mGluR-LTD that was indistinguishable from WT control mice (Fig. 1G–I). These findings suggested that suppression of eIF2α phosphorylation via the genetic removal of PERK in excitatory neurons improves AD-associated mGluR-LTD deficits.

3.3. Hippocampal mGluR-LTD impairments in APP/PS1 mice are rescued by a selective inhibitor of PERK

In addition to the genetic deletion of PERK, we used a pharmacological approach to examine the effects of repressing PERK/eIF2α signaling on the mGluR-LTD impairments in AD mice. Recently it was reported that a newly characterized and specific inhibitor of PERK (GSK2606414) rescued memory deficits and brain pathology in a mouse model of prion disease (Moreno et al., 2013), and brain pathology in a mouse model of frontotemporal dementia (Radford et al., 2015). Notably, in both of these studies, the rescuing effects of the PERK inhibitor were associated with inhibition of PERK/eIF2α signaling and restored levels of protein synthesis (Moreno et al., 2013, Radford et al., 2015). We first demonstrated that treatment of slices with GSK2606414 caused reduction of eIF2α phosphorylation, but did not affect levels of total eIF2α or PERK (Fig. 2A). Moreover, in slices from APP/PS1 mice treated with GSK2606414, DHPG-induced mGluR-LTD (Fig. 2B–D) was indistinguishable from WT control slices treated with the inhibitor (Fig. 2B–D). We further demonstrated that GSK2606414 by itself did not alter mGluR-LTD in WT slices (Fig. 2E–G) when compared to vehicle-treated WT slices (Fig. 2E–G). Additionally, the PERK inhibitor did not alter basal synaptic function in either WT or APP/PS1 mice, as indicated by the findings that neither fEPSP baseline nor synaptic input-output relationships was affected by GSK2606414 (Fig. 2H–J, and data not shown). Taken together, mGluR-LTD failure in APP/PS1 AD model mice can be rescued by PERK inhibitor GSK2606414.

Fig. 2
Hippocampal mGluR-LTD impairments in APP/PS1 AD model mice are rescued by the PERK inhibitor GSK2606414. (A) Levels of phospho-eIF2α were reduced in hippocampal slices treated with GSK2606414. Levels of total eIF2α and PERK were not affected ...

4. Discussion

Long-lasting forms of synaptic plasticity including LTP and LTD remain the prime molecular mechanisms associated with learning and memory (Malenka and Bear, 2004). This is consistent with the notion that AD, the most common form of dementia in elderly, has been called a disease of “synaptic failure” (Selkoe, 2002). Numerous studies have indicated that deficiencies in neuronal plasticity characterize an early and sustaining key pathophysiology in AD (Ma and Klann, 2012). Consequently, elucidation of the detailed molecular mechanisms by which the neuronal plasticity impairments occur may present important opportunities for therapeutic discoveries. Here we describe for the first time that mGluR-LTD, a form of synaptic plasticity implicated in cognitive function mechanisms (Lüscher and Huber, 2010), is inhibited in an aged AD mouse model. Importantly, AD-associated inhibition of mGluR-LTD was reversed by repressing the eIF2α kinase PERK with either genetic or pharmacological approaches.

Many studies have demonstrated that Aβ impacts both LTP (inhibition) and LTD (enhancement) that are NMDAR-dependent (Shankar et al., 2008, Li et al., 2009, Ma et al., 2014). In contrast, we found that exogenous Aβ application does not affect mGluR-LTD (Fig.1D–F). Besides factors that might be attributed to Aβ sources (synthetic vs. human extracts) and preparation (different oligomer species), our findings suggest that acute Aβ application targets mainly at signaling pathways connected to NMDAR-dependent neuronal plasticity. In contrast, hippocampal mGluR-LTD was impaired in aged APP/PS1 AD model mice (Fig. 1A–C), indicating that the chronic accumulation of Aβ with aging impairs cellular mechanisms underlying mGluR-LTD. One such mechanism could be de novo protein synthesis, which is essential for long-lasting synaptic plasticity, including both LTP and LTD, regardless of whether they are NMDAR- or mGluR-dependent (Richter and Klann, 2009). In agreement with this concept, repression of eIF2α kinase PERK in APP/PS1 mice, which improves de novo protein synthesis (Ma et al., 2013), can alleviate AD-associated mGluR-LTD defects (Fig. 1G–I and Fig.2). Of interest, it was reported that hippocampal mGluR-LTD was enhanced in PERK cKO mice at young ages (4–5 weeks) (Trinh et al., 2014). In contrast, here we observed normal mGluR-LTD in old (12–15 month) PERK cKO mice (Fig. 1G–I), suggesting aging-related alterations in the synaptic response to DHPG when PERK/eIF2α signaling is repressed. It also should be noted that to induce mGluR-LTD in aged mice, DHPG must be applied to slices at a concentration of 100 μM, compared to 50 μM DHPG used in young mice (Trinh et al., 2014). Therefore, the relatively high dose DHPG might cause a “ceiling” effect at synapses so that the activation of mGluR is either maximized or saturated, which is associated with the blunting of mGluR-LTD enhancement in PERK cKO mice (Fig. 1G–I) and WT mice treated with the PERK inhibitor (Fig.2). The four kinases for eIF2α (PERK, GCN2, PKR, and HRI) were initially categorized and named for their response to a different cellular stress associated with activation of a single kinase (Wek et al., 2006). However, accumulating evidence indicates that in situations such as oxidative stress, which is linked to AD pathogenesis, multiple eIF2α kinases (especially PERK and GCN2) are recruited either simultaneously or sequentially to help maintain cellular homeostasis (Zhan et al., 2004, Hamanaka et al., 2005). In agreement with this idea, genetically reducing the expression of either PERK or GCN2 was shown to improve NMDAR-LTP impairments in AD mice (Ma et al., 2013). Meanwhile, PERK appears to play a dominant role in controlling eIF2α activity in brain based on the findings that basal levels of eIF2α phosphorylation are decreased by PERK deletion but not by removal of genes for other eIF2α kinases such as GCN2 or PKR (Ma et al., 2013). Although future investigation of aging-dependent alterations in translational control via each of the eIF2α kinases is still required, therapeutics that normalize eIF2α phosphorylation has potential for treatment of AD and other neurodegenerative disorders.

Highlights

  • Hippocampal mGluR-LTD is impaired in APP/PS1 AD model mice
  • Exogenous synthetic Aβ application does not affect hippocampal mGluR-LTD.
  • Brain-specific deletion of PERK reverses mGluR-LTD failure in APP/PS1 mice.
  • Hippocampal mGluR-LTD impairments in APP/PS1 mice are rescued by PERK inhibitor.

Acknowledgments

This work was supported by National Institutes of Health grants K99 AG044469 and R00 AG044469 (T.M.), NS034007 (E.K.), and a grant from the BrightFocus Foundation (T.M.). The authors thank Karen Klein, MA, ELS (Biomedical Research Services Administration, Wake Forest University Health Sciences) for editing the manuscript.

Footnotes

Disclosure statement: The authors declare no conflict of interest.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • Costa-Mattioli M, Gobert D, Stern E, Gamache K, Colina R, Cuello C, Sossin W, Kaufman R, Pelletier J, Rosenblum K, Krnjević K, Lacaille J-C, Nader K, Sonenberg N. eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell. 2007;129:195–206. [PMC free article] [PubMed]
  • Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron. 2009;61:10–26. [PMC free article] [PubMed]
  • D’Amelio M, Cavallucci V, Middei S, Marchetti C, Pacioni S, Ferri A, Diamantini A, Zio DD, Carrara P, Battistini L, Moreno S, Bacci A, Ammassari-Teule M, Marie H, Cecconi F. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nat Neurosci. 2011;14:69–76. [PubMed]
  • Hamanaka RB, Bennett BS, Cullinan SB, Diehl JA. PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell. 2005;16:5493–5501. [PMC free article] [PubMed]
  • Hou L, Antion MD, Hu D, Spencer CM, Paylor R, Klann E. Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron. 2006;51:441–454. [PubMed]
  • Hu N-W, Nicoll AJ, Zhang D, Mably AJ, Tiernan O’Malley SAP, Terry C, Collinge J, Walsh DM, Rowan MJ. mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo. Nat Commun. 2014;5:3374. [PMC free article] [PubMed]
  • Huber KM, Kayser MS, Bear MF. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science. 2000;288:1254–1257. [PubMed]
  • Jacobsen JS, Wu C-C, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103:5161–5166. [PubMed]
  • Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng. 2001;17:157–165. [PubMed]
  • Kim J-H, Anwyl R, Suh Y-H, Djamgoz MBA, Rowan MJ. Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo. J Neurosci. 2001;21:1327–1333. [PubMed]
  • Klann E, Antion MD, Banko JL, Hou L. Synaptic plasticity and translation initiation. Learn Mem. 2004;11:365–372. [PubMed]
  • Klann E, Dever TE. Biochemical mechanisms for translational regulation in synaptic plasticity. Nat Rev Neurosci. 2004;5:931–942. [PubMed]
  • Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009;62:788–801. [PMC free article] [PubMed]
  • Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ. Soluble A{beta} Oligomers Inhibit Long-Term Potentiation through a Mechanism Involving Excessive Activation of Extrasynaptic NR2B-Containing NMDA Receptors. J Neurosci. 2011;31:6627–6638. [PMC free article] [PubMed]
  • Lüscher C, Huber KM. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron. 2010;65:445–459. [PMC free article] [PubMed]
  • Ma T, Chen Y, Vingtdeux V, Zhao H, Viollet B, Marambaud P, Klann E. Inhibition of AMP-activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid β J Neurosci. 2014;34:12230–12238. [PMC free article] [PubMed]
  • Ma T, Du X, Pick JE, Sui G, Brownlee M, Klann E. Glucagon-like Peptide-1 Cleavage Product GLP-1 (9–36) Amide Rescues Synaptic Plasticity and Memory Deficits in Alzheimer’s Disease Model Mice. J Neurosci. 2012;32:13701–13708. [PMC free article] [PubMed]
  • Ma T, Hoeffer CA, Capetillo-Zarate E, Yu F, Wong H, Lin MT, Tampellini D, Klann E, Blitzer RD, Gouras GK. Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer’s disease. PLoS One. 2010;5:e12845. [PMC free article] [PubMed]
  • Ma T, Hoeffer CA, Wong H, Massaad CA, Zhou P, Iadecola C, Murphy MP, Pautler RG, Klann E. Amyloid β-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide. J Neurosci. 2011;31:5589–5595. [PMC free article] [PubMed]
  • Ma T, Klann E. Amyloid b: Linking Synaptic Plasticity Failure to Memory Disruption in Alzheimer’s Disease. J Neurochem. 2012;120(Suppl 1):140–148. [PMC free article] [PubMed]
  • Ma T, Klann E. PERK: a novel therapeutic target for neurodegenerative diseases? Alzheimers Res Ther. 2014;6:30. [PMC free article] [PubMed]
  • Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E. Suppression of eIF2α kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci. 2013;16:1299–1305. [PMC free article] [PubMed]
  • Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004;44:5–21. [PubMed]
  • Megill A, Tran T, Eldred K, Lee NJ, Wong PC, Hoe H-S, Kirkwood A, Lee H-K. Defective Age-Dependent Metaplasticity in a Mouse Model of Alzheimer’s Disease. J Neurosci. 2015;35:11346–11357. [PMC free article] [PubMed]
  • Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, Mallucci GR. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med. 2013;5:206ra138. [PubMed]
  • Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature. 2012;485:507–511. [PMC free article] [PubMed]
  • Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–421. [PubMed]
  • Radford H, Moreno JA, Verity N, Halliday M, Mallucci GR. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol. 2015;130:633–642. [PMC free article] [PubMed]
  • Raymond CR, Ireland DR, Abraham WC. NMDA receptor regulation by amyloid-beta does not account for its inhibition of LTP in rat hippocampus. Brain Res. 2003;968:263–272. [PubMed]
  • Richter JD, Klann E. Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev. 2009;23:1–11. [PubMed]
  • Rosenberg T, Gal-Ben-Ari S, Dieterich DC, Kreutz MR, Ziv NE, Gundelfinger ED, Rosenblum K. The roles of protein expression in synaptic plasticity and memory consolidation. Front Mol Neurosci. 2014;7:86. [PMC free article] [PubMed]
  • Rowan MJ, Klyubin I, Wang Q, Anwyl R. Synaptic plasticity disruption by amyloid beta protein: modulation by potential Alzheimer’s disease modifying therapies. Biochem Soc Trans. 2005;33:563–567. [PubMed]
  • Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002;298:789–791. [PubMed]
  • Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008;14:837–842. [PMC free article] [PubMed]
  • Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T, Nishitsuji K, Ito K, Shimada H, Lambert MP, Klein WL, Mori H. A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci. 2010;30:4845–4856. [PubMed]
  • Trinh MA, Kaphzan H, Wek RC, Pierre P, Cavener DR, Klann E. Brain-Specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility. Cell Rep. 2012;1:676–688. [PMC free article] [PubMed]
  • Trinh MA, Klann E. Translational control by eIF2α kinases in long-lasting synaptic plasticity and long-term memory. Neurobiol Learn Mem. 2013;105:93–99. [PMC free article] [PubMed]
  • Trinh MA, Ma T, Kaphzan H, Bhattacharya A, Antion MD, Cavener DR, Hoeffer CA, Klann E. The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression. Learn Mem. 2014;21:298–304. [PubMed]
  • Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A, Wisniewski T, Koleske AJ, Gunther EC, Nygaard HB, Strittmatter SM. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron. 2013;79:887–902. [PMC free article] [PubMed]
  • Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid b protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–539. [PubMed]
  • Wang H-W, Pasternak JF, Kuo H, Ristic H, Lambert MP, Chromy B, Viola KL, Klein WL, Stine WB, Krafft GA, Trommer BL. Soluble oligomers of beta amyloid (1–42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 2002;924:133–140. [PubMed]
  • Wek RC, Cavener DR. Translational control and the unfolded protein response. Antioxid Redox Signal. 2007;9:2357–2371. [PubMed]
  • Wek RC, Jiang H-Y, Anthony TG. Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans. 2006;34:7–11. [PubMed]
  • Zhan K, Narasimhan J, Wek RC. Differential activation of eIF2 kinases in response to cellular stresses in Schizosaccharomyces pombe. Genetics. 2004;168:1867–1875. [PubMed]