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date: 17 February 2020

Dysregulation of Neuronal Protein Synthesis in Alzheimer’s Disease

Abstract and Keywords

Currently there is no effective cure or intervention available for Alzheimer’s disease (AD), a devastating neurodegenerative disease and the most common form of dementia. It is urgent to understand the basic cellular/molecular signaling mechanisms underlying AD pathophysiology to identify novel therapeutic targets and diagnostic biomarkers. Many studies indicate impaired synaptic function as a key and early event in AD pathogenesis. Mounting evidence suggests that dysregulations in mRNA translation (protein synthesis) may contribute to the development of synaptic dysfunction and cognitive defects in neurodegenerative diseases including AD. Protein synthesis happens in three phases (initiation, elongation, and termination) and is tightly controlled through regulation of multiple signaling pathways in response to various stimuli. Integral protein synthesis is indispensable for memory formation and maintenance of synaptic plasticity. Interruption of protein synthesis homeostasis can lead to impairments in cognition and synaptic plasticity. This chapter reviews recent studies supporting the idea that impaired protein synthesis is an important mechanism underlying AD-associated cognitive deficits and synaptic failure. It focuses on three signaling cascades controlling protein synthesis: eukaryotic initiation factor 2α (eIF2α), the mammalian target of rapamycin complex 1 (mTORC1), and eukaryotic elongation factor 2 (eEF2). Findings from human and animal studies demonstrating an association between dysregulation of these pathways and AD pathophysiology are summarized and discussed.

Keywords: Alzheimer’s disease, dementia, synaptic plasticity, protein synthesis, PERK, eIF2α phosphorylation, eEF2 phosphorylation, mTORC1, Alzheimer’s disease-related dementia

Introduction

Alzheimer’s disease (AD) is the most common form of dementia syndromes with aging as the greatest known risk factor (Alzheimer’s Association, 2019; Querfurth & LaFerla, 2010). Concomitant with the rapid growth of the aging population worldwide, the incidence of AD is escalating significantly, becoming a global threat to public health and a pressing “epidemic” for the 21st century Unfortunately, no interventions have been discovered to either slow the progress of AD or cure the disease, and recent clinical trials have not succeeded in identifying disease-modifying strategies (Dyer, Renner, & Bachmann, 2006; Holtzman, Goate, Kelly, & Sperling, 2011; Holtzman, Morris, & Goate, 2011; Roberson & Mucke, 2006). Thus, there is an urgent need to develop novel therapeutics targeting AD pathophysiology based on solid mechanistic studies.

The hallmarks of AD brain pathology include cerebral plaques and neurofibrillary tangles, which consist of aggregated β-amyloid peptide (Aβ) and abnormally hyper-phosphorylated tau proteins, respectively (Querfurth & LaFerla, 2010). Of note, while there is no doubt about the importance of Aβ and tau phosphorylation (p-tau) as biomarkers or pathological diagnostic criteria for AD, the exact roles of Aβ and tau phosphorylation in AD etiology are still under debate (Herrup, 2015; Ma & Klann, 2012; Tse & Herrup, 2017). Substantial evidence indicates synaptic dysfunction as a key event in AD pathophysiology, and accordingly AD has been called a disease of “synaptic failure” (Ma & Klann, 2012; Selkoe, 2002; Walsh & Selkoe, 2004). Understanding the molecular and cellular mechanisms underlying AD-associated synaptic dysfunction/failure will help identify novel diagnostic biomarkers and perhaps, more importantly, therapeutic targets for AD (Ma & Klann, 2012; Rowan, Klyubin, Wang, & Anwyl, 2005; Teich et al., 2015). Substantial evidence over the past few decades has established that long-lasting forms of synaptic plasticity (persistent change in neuronal circuits) and memory require de novo protein synthesis (or mRNA translation). Recent studies indicate an important role of mRNA translation impairments in AD-associated synaptic failure and cognitive defects (Beckelman et al., 2019; Jan et al., 2017; Ma et al., 2013). For this chapter, I will focus on several signaling pathways controlling protein synthesis and their roles (when dysregulated) in AD-associated dementia syndrome.

Role of eIF2α Phosphorylation in AD

Protein synthesis takes place in three phases: initiation, elongation, and termination. Each phase requires the action of multiple translational factors to facilitate the process. Translation is highly controlled at the initiation phase. During the initiation phase, eukaryotic initiation factor 2 (eIF2) binds GTP and Met–tRNAi Met to form a ternary complex to interact with the small ribosomal subunit. The exchange of GTP and GDP-bound form of the complex is catalyzed by another translational factor: eukaryotic initiation factor 2B (eIF2B). Phosphorylation of eIF2 on the α subunit (eIF2α) at the Ser51 site inhibits the catalytic function of eIF2B and consequently blocks the GDP/GTP exchange. Therefore, general protein synthesis is inhibited when there is increased phosphorylation of eIF2α (Klann & Dever, 2004; Richter, Bassell, & Klann, 2015; Trinh et al., 2014). On the other hand, eIF2α phosphorylation increases translation of a selective subset of mRNAs with upstream open reading frames (uORFs) in their 5′ untranslated region (UTR). One of the best known examples of such mRNAs encodes activating transcription factor 4 (ATF4), a repressor of long-term synaptic plasticity and memory formation (Costa-Mattioli, Sossin, Klann, & Sonenberg, 2009; Klann, Antion, Banko, & Hou, 2004; Trinh et al., 2014; R. Wek, 2018).

There are four known eIF2α kinases: double-stranded-RNA-dependent protein kinase (PKR); heme-regulated inhibitor kinase (HRI); general control non-derepressible-2 (GCN2), and PKR-like ER (endoplasmic reticulum) kinase (PERK; R.C. Wek, Jiang, & Anthony, 2006). As indicated in their names, the classic view of the eIF2α kinases considers that each kinase is activated by a specific type of stimulus or cellular stress (R. C. Wek & Cavener, 2007). However, it is oversimplified to conclude that one type of stressing stimulus activates only one eIF2α kinase. For example, during oxidative stress conditions, multiple eIF2α kinases, particularly PERK and GCN2, are recruited simultaneously or sequentially to cope with cellular homeostasis (Jiang et al., 2004; Zhan, Narasimhan, & Wek, 2004). Notably, each of the four kinases phosphorylates eIF2α on the same site Ser51 (Trinh & Klann, 2013).

Multiple studies indicate elevated eIF2α phosphorylation in neurodegenerative diseases and point to PERK suppression as a potential therapeutic strategy for cognitive impairments associated with these diseases (Ma & Klann, 2014; Moreno et al., 2012; Radford, Moreno, Verity, Halliday, & Mallucci, 2015). Accumulation of misfolded proteins represents one of the key brain pathologies of neurodegenerative diseases. These misfolded proteins cause significant cellular stress and induce activation of the signaling pathways associated with unfolded protein response (UPR). The UPR is composed of three key effectors: activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1), and PERK (Ronald C. Wek & Cavener, 2007). Dysregulations of signaling pathways associated with all three effectors (ATF6, IRE1, and PERK) have been indicated in AD (Cornejo & Hetz, 2013; Gerakis & Hetz, 2018; Hetz & Saxena, 2017). In this review I focus the discussion on PERK signaling, from the view of protein synthesis regulation (Figure 1). Activation of PERK leads to increased eIF2α phosphorylation and inhibition of general protein synthesis. Suppression of general protein synthesis temporarily can be beneficial, since it helps conserve energy resources while enhancing translation of mRNAs related to anti-stress response (e.g., ATF4), thus preparing cells to cope with stress (Ma & Klann, 2014; Paschen, Proud, & Mies, 2007). During the pathogenesis of certain neurodegenerative diseases (e.g., AD), however, activation of PERK and eIF2α phosphorylation persist as a result from severe cellular stress and UPR, causing prolonged repression of protein synthesis. Prolonged elevation of eIF2α phosphorylation and inhibition of mRNA translation are detrimental because long-lasting forms of synaptic plasticity and memory formation/consolidation are dependent on de novo protein synthesis (Alberini, 2008; Costa-Mattioli et al., 2009; Kelleher, Govindarajan, & Tonegawa, 2004).

Dysregulation of Neuronal Protein Synthesis in Alzheimer’s Disease

Figure 1. Schematic model depicting potential links of eIF2α phosphorylation and eIF2α kinases to AD. Briefly, AD-associated pathological processes induce ER stress and unfolded protein response (UPR), leading to activation of eIF2α kinase PERK. Phosphorylation of eIF2α by PERK results in inhibition of general protein synthesis (mRNA translation), and protein synthesis is required for memory formation and long-lasting forms of synaptic plasticity. Arrows denote activation and blunted lines indicate inhibition.

AD is characterized by ER stress and aberrant signaling associated with UPR. In agreement, abnormal hyper-phosphorylation of eIF2α has been identified in brains of AD patients and in AD model mice (Chang, Wong, Ng, & Hugon, 2002; Kim et al., 2010; Ma et al., 2013; O'Connor et al., 2008). To study whether elevated eIF2α phosphorylation contributes to AD pathophysiology, investigators reduce brain eIF2α phosphorylation in a mouse model of AD by genetically suppressing eIF2α kinase PERK in neurons of the forebrain and hippocampus (Ma et al., 2013). They found that spatial memory impairments displayed in aged AD model mice were significantly improved by genetic reduction of PERK. Furthermore, AD-associated defects in hippocampal long-term potentiation (LTP), one of the most intensively studied forms of synaptic plasticity that is considered as a cellular model for memory, were also improved with PERK suppression. In addition, they demonstrated that application of the general protein synthesis inhibitor anisomycin was able to reverse the LTP improvement associated with PERK suppression, indicating that the beneficial effects of reducing eIF2α phosphorylation on AD-associated synaptic failure are dependent on protein synthesis (Ma et al., 2013). Long-term depression (LTD) is another important form of synaptic plasticity that is known to be impaired in AD (S. Li et al., 2009). Studies suggest that metabotropic glutamate receptor 5 (mGluR5) may mediate the neurotoxic effects of Aβ (Hu et al., 2014; Um et al., 2013). It was later demonstrated that mGluR-LTD failure in AD model mice can also be alleviated by suppressing PERK activity genetically or pharmacologically using small molecule PERK antagonist GSK2606414 (W. Yang, Zhou, Cavener, Klann, & Ma, 2016).

As a novel and selective PERK inhibitor, GSK2606414 holds promise as a potential treatment for neurodegenerative diseases. Moreno and colleagues treated prion disease model mice with GSK2606414 before or after the occurrence of clinical symptoms, and found marked improvement in both behavior deficiency and brain pathology associated with the prion disease (Moreno et al., 2013). The same group also showed that treatment of GSK2606414 is effective in preventing tau-mediated neuropathology and behavioral defects in a mouse model of frontotemporal dementia (FTD; Radford et al., 2015).

There are several caveats in proposing PERK inhibition as a therapeutic strategy for AD or other neurodegenerative diseases. Regulation of PERK is critical for normal pancreatic function, maintenance of glucose homeostasis, and development of skeletal system (P. Zhang et al., 2002). For example, a mutation in the gene encoding PERK (EIF2AK3) is linked to Wolcott-Rallison syndrome in humans, which is characterized by neonatal diabetes mellitus (Sene´e et al., 2004). Consistently, it was reported that oral treatment of GSK2606414 in mice caused hyperglycemia and weight loss (Moreno et al., 2013). These non-neuronal harmful side effects have to be considered when PERK inhibitors are applied systematically. Moreover, it was reported that brain-specific suppression of PERK in mice leads to significant impairments in cognition including severe behavioral inflexibility (Trinh et al., 2012), which could be related to the roles of PERK in handling cellular stress. Studies also show that interruption of eIF2α phosphorylation homeostasis in mice leads to impaired behavioral and neuronal plasticity (Costa-Mattioli et al., 2007). Therefore, in order for PERK inhibition to be a viable therapeutic approach, it is critical to optimize the dose and duration of PERK inhibitor treatment to “normalize” eIF2α phosphorylation, thus keeping a balance between de novo protein synthesis (for learning and memory) and maintaining essential UPR response under stressing conditions.

Dysregulation of mTORC1 Signaling and AD

mTOR (mammalian target of rapamycin, also known as mechanistic target of rapamycin) is an evolutionarily conserved protein kinase that plays a critical role in cell growth and protein synthesis (Albert & Hall, 2015; Laplante & Sabatini, 2012). Depending on the binding proteins associated with mTOR and sensitivity to rapamycin, mTOR assembles into two complexes, mTORC1 (mammalian target of rapamycin complex 1) and mTORC2 (mammalian target of rapamycin complex 2; Albert & Hall, 2015; Hoeffer & Klann, 2010; Q. Yang & Guan, 2007). Briefly, mTORC1 contains raptor, an essential and non-enzymatic subunit of the complex that is required for rapamycin’s inhibitory effect, and mLST8, which binds to the kinase domain of mTOR. The interactions between mTOR, raptor, and mLST8 are thought to determine the access of mTOR to its downstream targets (Q. Yang & Guan, 2007). Most studies reported so far on AD focus on regulation of mTORC1 only.

One known upstream regulator of mTORC1 involves PI3K signaling pathway through the tuberous sclerosis complex, consisting of TSC1 (hamartin) and TSC2 (tuberin). The 3′-phosphoinositides PI(3,4)P2 and PI(3,4,5)P3, produced by PI3K, bind to the pleckstrin homology domain of the Ser/Thr kinase AKT (PKB) and recruit it to the membrane. There, AKT can be phosphorylated at Thr308 in its activation loop by phosphoinositide-dependent-kinase 1 (PDK1), which also has a pleckstrin homology domain. In addition to its phosphorylation at Thr308, AKT can be phosphorylated on the hydrophobic motif site Ser473 by a kinase initially referred as “PDK2” but of unknown identity. This kinase was later demonstrated to be the long-sought mTORC2. While the activity of AKT can be potentiated significantly by phosphorylation at Ser473, Thr308 phosphorylation is thought to be both necessary and sufficient for TSC2 phosphorylation (Fruman et al., 2017; Manning & Cantley, 2007; Q. Yang & Guan, 2007). Besides AKT, multiple signaling molecules are known to regulate mTORC1 activity directly or via TSC2 including p90 ribosomal S6 kinase (RSK), MAPK/ERK, AMP-activated protein kinase (AMPK), and glycogen synthase kinase-3 (GSK3). Compared to AKT and ERK which are positive regulators of mTORC1, both AMPK and GSK3 are negative regulators of mTORC1 (i.e., activation of AMPK or GSK3 results in suppression of mTORC1 signaling; Choo, Roux, & Blenis, 2006). Probably the best known downstream targets of mTORC1 are S6K1 (or p70S6K) and a repressor protein of eukaryotic initiation factor 4E (eIF4E) named 4EBP (eIF4E binding protein) (Hoeffer & Klann, 2010). Translation is highly regulated at the initiation step during which a ribosome is recruited to the 5′ end of an mRNA, which in all nuclear-transcribed mRNAs possesses the cap structure m7GpppN (where “m” represents a methyl group and “N” refers to any nucleotide). The cap is specifically recognized and bound by eIF4E, which is a subunit of a complex termed eIF4F that contains two other proteins: eIF4G (a scaffolding protein) and eIF4A (an RNA helicase). Following its binding to the 5′cap, eIF4F (attached to the 40S subunit through an interaction between eIF4G and eIF3) is thought to melt the secondary structure of the 5′‑UTR, thereby facilitating scanning to the start codon, where the 60S subunit joins and translation commences. The initiation factor eIF4B, which enhances the helicase activity of eIF4A, also contributes to removing the secondary structure of the transcript (Gingras et al., 1999). S6K1, on the other hand, plays a critical role in regulation of cell size and glucose homeostasis (Meyuhas & Dreazen, 2009). S6K1 has eight known phosphorylation sites distributed in three functional domains—catalytic, linker, and auto-inhibitory. At least five of the phosphorylation sites—Thr229, Thr389, Ser404, Ser411, and Ser421—are sensitive to rapamycin, among which Thr389 is reported to be phosphorylated by mTORC1 and is often used as a readout for mTORC1 signaling regulation (Fumagalli & Thomas, 2000; Lehman, Calvo, & Gomez-Cambronero, 2003; Loreni, Thomas, & Amaldi, 2000; Y. Zhang et al., 2001). Moreover, mTOR signaling mediates translation of a specific class of mRNAs characterized by presence of the terminal oligopyrimidine (TOP) at their 5′ end. Interestingly, many of the TOP mRNAs encode components of the “translational machinery” including ribosomal proteins and elongation factors (e.g., eEF1A). Thus, activation of the mTOR pathway is considered to increase translational capacity (Hay & Sonenberg, 2004; Meyuhas, 2000; Panayiotis Tsokas, Ma, Iyengar, Landau, & Blitzer, 2007).

Numerous studies have demonstrated a key role of mTORC1 in neuronal function. The activation of mTORC1 signaling and the consequent boost of translational capacity and cap-dependent translation initiation are crucial for memory consolidation and long-lasting forms of synaptic plasticity. A plethora of studies using genetically modified mice or pharmacological agents (e.g., rapamycin) demonstrated that integral mTORC1 signaling is required for normal learning, memory and synaptic plasticity (Graber, McCamphill, & Sossin, 2013; Hoeffer & Klann, 2010).

Multiple lines of evidence indicate a role of mTORC1 signaling dysregulation and AD pathophysiology; although controversy arises regarding how exactly mTORC1 signaling is dysregulated in AD. Downregulation of the mTORC1 signaling was reported in APP/PS1 AD model mice. Consistently, the mTORC1 inhibitor rapamycin exacerbates Aβ neurotoxicity (Lafay-Chebassier et al., 2005; Lafay-Chebassier et al., 2006). In Tg2576 AD model mice, it was revealed that brain mTORC1 signaling, assessed by S6K1 activity, is decreased at young (3-month-old) and middle-aged (9-month-old) mice, but unaltered in old mice (over 20-month- old; Ma et al., 2010). In agreement, levels of elongation factor eEF1A, one of the “TOP” mRNA encoded proteins controlled by mTORC1/S6K1 signaling that is indicated in long-lasting synaptic plasticity, are also reduced in AD (Beckelman et al., 2016; P. Tsokas et al., 2005). In contrast, elevated mTORC1 signaling is reported in the 3XTg-AD model mice (Caccamo, Majumder, Richardson, Strong, & Oddo, 2010). Moreover, a study on the PDAPP (known as J20) AD model mice reported no change in mTORC1 signaling (Spilman et al., 2010). mTORC1 functions as a “hub” to integrate many signaling cascades in response to diverse stimuli such as stress, energy status alteration, and inflammation (Hoeffer & Klann, 2010; Reiling & Sabatini, 2006). It is likely that certain differences in generation of AD models may contribute to the discrepancies in regulation of mTORC1 signaling. For example, mutations in tau (in 3xTg-AD model mice) may induce unique regulation of mTORC1 pathway, or alter the response of the mTORC1 signaling to Aβ. In line with such inconsistency on mTORC1 dysregulation in AD, there is also debate on whether mTORC1 should be inhibited or activated for treatment of AD-associated cognition deficits and synaptic failure (Ma & Klann, 2012; Talboom, Velazquez, & Oddo, 2015).

Aging is one of the best known risk factors for AD. Several studies in late 2000 on the association between the mTORC1 signaling and mammalian aging garnered a lot of attention from the AD research field. One study in mice showed that genetic deletion of S6K1, an established downstream effector of mTORC1, resulted in increased life span and resistance to multiple age-related pathologies including immune and motor dysfunction, and insulin insensitivity (Selman et al., 2009). In agreement, another study published in the same year showed that aged mice fed with rapamycin live longer than control groups (Harrison et al., 2009). Worth mentioning is that neither studies addressed whether aging-related decline in synaptic plasticity and cognition are improved by inhibiting mTORC1 signaling. A later study reported that while rapamycin may extend life span, it has limited beneficial effects on aging phenotypes. In another words, the longevity effects of rapamycin feeding might be due to its drug effects unrelated to aging such as cancer limiting effects (Neff et al., 2013). In two lines of AD model mice, treatment with rapamycin for over two months was able to rescue AD-associated cognitive deficits (Caccamo et al., 2010; Spilman et al., 2010). In agreement, genetic suppression of mTOR or S6K1 prevented cognitive impairments and brain pathology in AD model mice (Caccamo et al., 2015; Caccamo, Pinto, Messina, Branca, & Oddo, 2014). On the other hand, it was reported that hippocampal synaptic plasticity impairments caused by Aβ application are reversed by up-regulating mTORC1 signaling via pharmacological methods or genetic manipulation such as suppression of TSC2 or FK506-binding protein 12 (FKBP12), both of which are negative regulators of mTORC1 (Hoeffer et al., 2008; Ma et al., 2010). Several reasons may explain the seemingly conflicting findings regarding the relationship between mTORC1 signaling regulation and AD pathophysiology. First, in the aforementioned studies using rapamycin, mTORC1 signaling was manipulated differently (e.g., different dose and duration of treatment). For example, while mTORC2 usually is considered rapamycin-insensitive, prolonged treatment of rapamycin can lead to inhibition of mTORC2 and consequently interference of AKT signaling, which functions as an upstream regulator of mTORC1 (Sarbassov et al., 2006). Moreover, several feedback loops exist in the mTORC1 signaling pathway such as the reciprocal effects between S6K1 and AMPK, a central molecular energy sensor functioning to maintain cellular energy homeostasis, dysregulation of which is indicated in AD (Hardie, 2014; Ma et al., 2014; Selman et al., 2009). Thus, the effects of mTORC1 manipulation on AD might be attributed to influence from feedback or compensatory regulations (Selman et al., 2009). The complexity of mTORC1 signaling regulation in AD can also be demonstrated by studies on roles of insulin in neuronal diseases. Insulin activates the PI3K-PDK-AKT cascade, which is upstream of mTORC1 (Arnold et al., 2018; Piper, Selman, McElwee, & Partridge, 2008). Insulin-PI3K-PDK-AKT signaling is impaired by Aβ treatment (De Felice et al., 2009; Lee, Kumar, Fu, Rosen, & Querfurth, 2009; Magrané et al., 2005; Townsend, Mehta, & Selkoe, 2007). Also, insulin treatment can improve cognitive function in AD patients (Craft et al., 2012; Reger et al., 2008). On the other hand, suppression of insulin signaling can protect a transgenic mouse model of AD from cognitive decline (Cohen et al., 2009). To summarize, the role of mTORC1 signaling in AD remain unclear, and further investigation is necessary to determine whether rapamycin can be considered as a feasible treatment for AD.

Role of eEF2K/eEF2 Signaling in AD

As discussed earlier, eIF2α phosphorylation and mTORC1 signaling play vital roles in controlling the initiation phase of mRNA translation. While much attention has been devoted to the initiation process for translational control, accumulating evidence indicates that control at the elongation phase is critical in modulation of protein synthesis during cellular responses to deficiency of nutrients and energy. In fact, most (> 95%) of the energy and amino acids used in protein synthesis are consumed during the elongation phase (Browne & Proud, 2002; Kenney, Moore, Wang, & Proud, 2014). Elongation is primarily regulated through the eukaryotic elongation factor 2 kinase (eEF2K), the only known kinase for eEF2. Phosphorylation of eEF2 on Thr56 by eEF2K prevents it from binding to the ribosome, thus disrupting peptide growth and general protein synthesis (Kenney et al., 2014). Selective eEF2K inhibitors, such as NH125, AG-484954 and JAN-384, have been developed, but have not yet been tested in vivo for effects on AD-related abnormalities (Arora et al., 2003; Arora et al., 2004; Chen et al., 2011; Kenney et al., 2016). Previous studies, mostly from non-neuronal systems, have identified multiple signaling molecules as upstream regulators in the eEF2K-eEF2 signaling network, including mTORC1 and AMPK (Hardie, 2004, 2014; Horman et al., 2002). In brief, the mTORC1 inhibits activity of eEF2K via phosphorylation, either directly or indirectly through its downstream effector S6K1. Thus, activation of mTORC1 leads to dephosphorylation of eEF2 and consequently promotion of translation elongation, which, in concert with mTORC1-controlled translation initiation, allows the stimulation of general protein synthesis. In contrast, AMPK stimulates activity of eEF2K, either via phosphorylating eEF2K (on a different site from mTORC1), or by inhibiting mTORC1 activity, leading to eEF2 phosphorylation and thus suppression of general protein synthesis (Kenney et al., 2014). AMPK is a central molecular sensor critical for maintenance of cellular energy homeostasis, and AMPK activity is important in maintaining long-lasting forms of synaptic plasticity (Potter et al., 2010). AMPK is activated in response to low-energy state, and AD pathogenesis has been linked to abnormalities in neuronal energy metabolism (Lin & Beal, 2006; Ma et al., 2012; Ma & Klann, 2012; Massaad, Washington, Pautler, & Klann, 2009). Consistently, over-activation of AMPK has been revealed in brain tissue of AD mouse models and human AD patients (Ma et al., 2014; Vingtdeux, Davies, Dickson, & Marambaud, 2011). Most recently it was reported that repression of AMPK activity either pharmacologically or genetically results in mitigation of AD-related impairments of hippocampal LTP, a well-studied synaptic model for learning and memory (Ma et al., 2014). Furthermore, inhibition of LTP by application of amyloid beta (Aβ) is also linked to reducing kinase activity of AKT/PKB, a canonical upstream regulator for both mTORC1 (stimulation) and AMPK (inhibition; Figure 2.) It was reported that the reduction of AKT activity in AD results from increased caspase-3 activity associated with reactive oxygen species (ROS), which is implicated in many neurodegenerative diseases (Dumont et al., 2009; Jo et al., 2011).

Dysregulation of Neuronal Protein Synthesis in Alzheimer’s Disease

Figure 2. Schematic model of eEF2K/eEF2 signaling and its potential link to AD. Phosphorylation of eEF2 by eEF2K results in repression of general protein synthesis (mRNA translation). AMP-activated protein kinase (AMPK) activates eEF2K and thus increases eEF2 phosphorylation. In contrast, mammalian target of rapamycin complex 1 (mTORC1) inhibits eEF2K activity and decreases eEF2 phosphorylation, either directly or via its downstream target S6K1. NH125 and AG-484594 (or A-484594) are both selective inhibitors of eEF2K.

Regulation of protein synthesis via elongation is particularly important in cellular environments where the translational capacity is low (e.g., neuronal dendrites), thus both initiation and elongation processes need to be upregulated to fulfill the substantial requirements of new protein synthesis associated with synaptic plasticity (Sutton & Schuman, 2006). For example, it was demonstrated that treatment of neurons with brain-derived neurotrophic factor (BDNF), a key player in neuronal plasticity, reduced eEF2 phosphorylation, leading to promotion of translation elongation and general protein synthesis (Takei et al., 2009). Moreover, it was recently reported that eEF2K-eEF2 signaling controls synthesis of microtubule-related proteins, which play an important role in regulating dendritic spine morphology that is modified during synaptic plasticity, learning and memory (Kenney et al., 2016). In transgenic eEF2K homozygous knockout mice, late, protein synthesis-dependent LTP is enhanced (Park et al., 2008). As for LTD, another form of synaptic plasticity, genetic deletion of eEF2K results in defects in mGluR-LTD, but does not alter LTD that is N-methyl-D-aspartate (NMDA) receptor-dependent (Park et al., 2008). Interestingly, while phosphorylation of eEF2 (particularly via PKA activation) decreases general protein synthesis, it can increase translation of certain mRNAs including those for Arc and αCaMKII, which may play important roles in mGluR-LTD (Park et al., 2008; Taha, Gildish, Gal-Ben-Ari, & Rosenblum, 2013). Conversely, LTP is impaired in transgenic mice in which eEF2K is overexpressed (Im et al., 2009). Consistently, transgenic mice with eEF2K overexpression display impaired long-term contextual fear memory, but normal long-term cued fear memory. In addition, long-term hippocampus-dependent spatial memory, as assessed by the Morris water maze test, is also impaired in transgenic mice overexpressing eEF2K (Im et al., 2009).

Recent studies demonstrated abnormal hyper-phosphorylation of eEF2 (Thr56 site) in brain tissues of multiple lines of AD model mice, and in post mortem brain tissues from AD patients (Jan et al., 2017; X. Li, Alafuzoff, Soininen, Winblad, & Pei, 2005; Ma et al., 2014). Furthermore, hippocampal LTP failure induced by Aβ is rescued by the eEF2K inhibitor NH125 (Ma et al., 2014). In agreement, studies conducted in primary cultured neurons show that repression of eEF2K activity using compound A-484594 (a selective eEF2K inhibitor structurally distinct from NH125) or a genetic knockdown approach (shRNAs) alleviate the neurotoxic effects of Aβ on dendrite formation and cell viability (Jan et al., 2017). In a recent report, eEF2K is suppressed with genetic approaches in two separate lines of AD model mice. The hypothesis to be tested is whether suppression of eEF2 phosphorylation (via eEF2K inhibition) can alleviate AD-associated pathophysiology. First, it was found that AD-associated de novo protein synthesis deficits in hippocampi are improved by eEF2K suppression. Using multiple behavioral assays, the investigators demonstrated that cognitive defects in aged AD model mice are alleviated with repression of eEF2K. Consistently, hippocampal LTP impairments displayed in AD model mice are also mitigated by eEF2K knockdown. Interestingly, AD brain pathology including Aβ plaques and tau phosphorylation is unaltered with eEF2K inhibition. Moreover, reducing eEF2K results in alleviation of AD-related deficits in postsynaptic density formation, dendritic spine morphology, and dendritic polyribosome (clusters of ribosomes involved in active mRNA translation) assembly (Beckelman et al., 2019).

Conclusion

AD is the most common form of dementia syndromes without any cure currently available. Elucidation of the molecular mechanisms underlying AD etiology would provide important insights for the development of novel therapeutic targets and diagnostic biomarkers. Emerging evidence indicate an important role of protein synthesis dysregulation in AD pathophysiology. Recent studies suggest that boosting overall protein synthesis capacity via manipulation of multiple signaling pathways controlling mRNA translation can confer beneficial effects to AD-associated cognitive impairments and synaptic failure, thus representing a potential therapeutic strategy for AD and related dementia syndromes.

Future Perspectives

  1. 1. Both hypoactive and hyperactive protein synthesis are associated with impairments of cognitive function and synaptic plasticity. While boosting general protein synthesis could be a promising therapeutic strategy for AD, it is critical to fine-tune the treatment paradigm to avoid significant side effects due to interruption of mRNA translation homeostasis.

  2. 2. AD is a multifactorial disease that may involve dysregulation of multiple body systems. It would be interesting to determine whether better outcomes arise from targeting protein synthesis at the level of whole body or brain only. Along the same line, it would be intriguing to investigate the effects of manipulating protein synthesis “locally” (i.e., at dendrites or synapses), or in non-neuronal cells such as astrocytes and microglia.

  3. 3. In addition to general protein synthesis, it would be important to elucidate whether specifically targeting mRNA translation of plasticity-related proteins would be an effective therapeutic avenue. Findings from comprehensive, large-scale proteomics studies are expected to contribute significantly to the field.

  4. 4. Many studies using genetic approaches discussed in this chapter are elegantly designed and performed. Meanwhile, it is important to design and develop small molecule agents targeting protein synthesis regulation with minimal off-target effects to help advance the studies to human trials.

  5. 5. There is also an urgent need to develop diagnostic biomarkers for AD, especially at its early stage. Future studies, particularly in humans, are necessary to determine the correlation between dysregulations of signaling molecules discussed in this chapter (eIF2α, eEF2, etc.) and AD.

  6. 6. It is attractive to apply the strategy of targeting protein synthesis dysregulation to other AD-related dementia (ADRD).

Acknowledgments

I thank Antoine Almonte for comments and help in editing the manuscript. T. M. is supported by National Institutes of Health grants R01 AG055581 and R01 AG056622; the Alzheimer’s Association grant NIRG-15-362799; the BrightFocus Foundation grant A2017457S; and Wake Forest University School of Medicine. I apologize for those authors whose studies were not discussed in this manuscript due to space limitation.

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