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• W2034632760 abstract "•TNF-α mediates Aβ oligomer-induced PKR activation, eIF2α-P, and IRS-1 inhibition•Aβ oligomers impact synapses and memory via a TNF-α/PKR/eIF2α-P pathway•eIF2α phosphorylation induces synapse loss and memory deficit in mice•Bolstering insulin signaling suppresses the PKR/eIF-2α pathway Alzheimer’s disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that β-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR−/− and TNFR1−/− mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss. Alzheimer’s disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that β-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR−/− and TNFR1−/− mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss. Recent evidence suggests that Alzheimer’s disease (AD) is a novel, brain-specific form of diabetes (de la Monte and Wands, 2008de la Monte S.M. Wands J.R. Alzheimer’s disease is type 3 diabetes-evidence reviewed.J. Diabetes Sci. Tech. 2008; 2: 1101-1113Crossref PubMed Scopus (738) Google Scholar, De Felice, 2013De Felice F.G. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications.J. Clin. Invest. 2013; 123: 531-539Crossref PubMed Scopus (247) Google Scholar). AD brains exhibit defective insulin signaling with altered levels and cellular distribution of insulin receptors (Moloney et al., 2010Moloney A.M. Griffin R.J. Timmons S. O’Connor R. Ravid R. O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling.Neurobiol. Aging. 2010; 31: 224-243Abstract Full Text Full Text PDF PubMed Scopus (563) Google Scholar). Insulin signaling is central to neuronal survival, regulation of synapse number, and dendritic plasticity (van der Heide et al., 2005van der Heide L.P. Kamal A. Artola A. Gispen W.H. Ramakers G.M.J. Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner.J. Neurochem. 2005; 94: 1158-1166Crossref PubMed Scopus (195) Google Scholar, Chiu et al., 2008Chiu S.-L. Chen C.-M. Cline H.T. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo.Neuron. 2008; 58: 708-719Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, McNay and Recknagel, 2011McNay E.C. Recknagel A.K. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes.Neurobiol. Learn. Mem. 2011; 96: 432-442Crossref PubMed Scopus (147) Google Scholar), raising the possibility that deficient insulin signaling may be linked to neuronal dysfunction in AD. β-amyloid oligomers (AβOs), toxins that accumulate in AD brains and instigate synapse damage (Ferreira and Klein, 2011Ferreira S.T. Klein W.L. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease.Neurobiol. Learn. Mem. 2011; 96: 529-543Crossref PubMed Scopus (344) Google Scholar), remove insulin receptors from the neuronal surface (Zhao et al., 2008Zhao W.Q. De Felice F.G. Fernandez S. Chen H. Lambert M.P. Quon M.J. Krafft G.A. Klein W.L. Amyloid beta oligomers induce impairment of neuronal insulin receptors.FASEB J. 2008; 22: 246-260Crossref PubMed Scopus (471) Google Scholar, De Felice et al., 2009De Felice F.G. Vieira M.N.N. Bomfim T.R. Decker H. Velasco P.T. Lambert M.P. Viola K.L. Zhao W.Q. Ferreira S.T. Klein W.L. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers.Proc. Natl. Acad. Sci. USA. 2009; 106: 1971-1976Crossref PubMed Scopus (544) Google Scholar) and activate c-Jun N-terminal kinase (JNK) to trigger insulin receptor substrate (IRS-1) inhibition (Bomfim et al., 2012Bomfim T.R. Forny-Germano L. Sathler L.B. Brito-Moreira J. Houzel J.C. Decker H. Silverman M.A. Kazi H. Melo H.M. McClean P.L. et al.An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers.J. Clin. Invest. 2012; 122: 1339-1353Crossref PubMed Scopus (643) Google Scholar). These findings provided initial clues on how impaired neuronal insulin signaling develops in AD (De Felice, 2013De Felice F.G. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications.J. Clin. Invest. 2013; 123: 531-539Crossref PubMed Scopus (247) Google Scholar). Landmark studies from the diabetes field have established that activation of proinflammatory tumor necrosis factor alpha and JNK signaling (TNF-α/JNK signaling) is a key mechanism leading to peripheral insulin resistance (Hotamisligil et al., 1994Hotamisligil G.S. Budavari A. Murray D. Spiegelman B.M. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-α.J. Clin. Invest. 1994; 94: 1543-1549Crossref PubMed Scopus (731) Google Scholar, Hotamisligil et al., 1996Hotamisligil G.S. Peraldi P. Budavari A. Ellis R. White M.F. Spiegelman B.M. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance.Science. 1996; 271: 665-668Crossref PubMed Scopus (2200) Google Scholar, Gregor and Hotamisligil, 2011Gregor M.F. Hotamisligil G.S. Inflammatory mechanisms in obesity.Annu. Rev. Immunol. 2011; 29: 415-445Crossref PubMed Scopus (2528) Google Scholar). Therefore, it is likely that a molecular parallel exists between defective brain insulin signaling in AD and peripheral insulin resistance in diabetes (Bomfim et al., 2012Bomfim T.R. Forny-Germano L. Sathler L.B. Brito-Moreira J. Houzel J.C. Decker H. Silverman M.A. Kazi H. Melo H.M. McClean P.L. et al.An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers.J. Clin. Invest. 2012; 122: 1339-1353Crossref PubMed Scopus (643) Google Scholar, De Felice, 2013De Felice F.G. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications.J. Clin. Invest. 2013; 123: 531-539Crossref PubMed Scopus (247) Google Scholar). The double-stranded RNA-dependent protein kinase (PKR) is a critical player in the integration of an inflammatory response that leads to peripheral insulin resistance in metabolic disorders, including diabetes (Ozcan et al., 2004Ozcan U. Cao Q. Yilmaz E. Lee A.H. Iwakoshi N.N. Ozdelen E. Tuncman G. Görgün C.Z. Glimcher L.H. Hotamisligil G.S. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.Science. 2004; 306: 457-461Crossref PubMed Scopus (2978) Google Scholar, Hotamisligil, 2010Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.Cell. 2010; 140: 900-917Abstract Full Text Full Text PDF PubMed Scopus (2090) Google Scholar, Nakamura et al., 2010Nakamura T. Furuhashi M. Li P. Cao H. Tuncman G. Sonenberg N. Gorgun C.Z. Hotamisligil G.S. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis.Cell. 2010; 140: 338-348Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar). Elevated levels of phosphorylated PKR and of its key target, eukaryotic translation initiation factor 2α (eIF2α), have been reported in AD brains and in animal models of AD (Hoozemans et al., 2009Hoozemans J.J.M. van Haastert E.S. Nijholt D.A.T. Rozemuller A.J.M. Eikelenboom P. Scheper W. The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus.Am. J. Pathol. 2009; 174: 1241-1251Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar, Yoon et al., 2012Yoon S.O. Park D.J. Ryu J.C. Ozer H.G. Tep C. Shin Y.J. Lim T.H. Pastorino L. Kunwar A.J. Walton J.C. et al.JNK3 perpetuates metabolic stress induced by Aβ peptides.Neuron. 2012; 75: 824-837Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). eIF2α phosphorylation is critical for memory regulation (Costa-Mattioli et al., 2007Costa-Mattioli M. Gobert D. Stern E. Gamache K. Colina R. Cuello C. Sossin W. Kaufman R. Pelletier J. Rosenblum K. et al.eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory.Cell. 2007; 129: 195-206Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar) and has been recently shown to mediate prion-related neurodegeneration in the hippocampus (Moreno et al., 2012Moreno J.A. Radford H. Peretti D. Steinert J.R. Verity N. Martin M.G. Halliday M. Morgan J. Dinsdale D. Ortori C.A. et al.Sustained translational repression by eIF2α-P mediates prion neurodegeneration.Nature. 2012; 485: 507-511Crossref PubMed Scopus (453) Google Scholar), a memory center that is affected early in AD. Given the pathophysiological roles of TNF-α and PKR in peripheral insulin resistance (Nakamura et al., 2010Nakamura T. Furuhashi M. Li P. Cao H. Tuncman G. Sonenberg N. Gorgun C.Z. Hotamisligil G.S. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis.Cell. 2010; 140: 338-348Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar, Gregor and Hotamisligil, 2011Gregor M.F. Hotamisligil G.S. Inflammatory mechanisms in obesity.Annu. Rev. Immunol. 2011; 29: 415-445Crossref PubMed Scopus (2528) Google Scholar), we investigated here whether similar proinflammatory mechanisms might underlie neuronal dysfunction in AD. We hypothesized that the TNF-α pathway might cause phosphorylation of PKR and eIF2α-P, IRS-1 inhibition, and impact synapses and memory in AD. We show that phospho-PKR and eIF2α-P are elevated in the brains of a transgenic mouse model of AD, of mice and cynomolgus monkeys given intracerebroventricular (i.c.v.) infusions of AβOs, and in cultured hippocampal neurons exposed to oligomers. AβOs failed to trigger eIF2α-P and cognitive impairment in both PKR−/− and TNFR1−/− mice, as well as in mice treated with infliximab, a TNF-α neutralizing antibody. Salubrinal and thapsigargin, agents that increase eIF2α-P levels and endoplasmic reticulum (ER) stress, respectively, induced memory impairment in mice. Insulin treatment prevented oligomer-induced phosphorylation of PKR and eIF2α-P in hippocampal cultures. Glucagon-like peptide 1 (GLP-1) receptor agonists blocked eIF2α-P in hippocampal cultures and in the brains of transgenic mice and oligomer-injected monkeys. Collectively, results provide the grounds for targeting TNF-α/PKR/eIF2α-P signaling as a potential disease-modifying therapy for AD. We first explored whether AβOs abnormally activate the unfolded protein response (UPR), which has been described to intersect with inflammatory and stress signaling pathways that lead to peripheral insulin resistance in chronic metabolic diseases (Ozcan et al., 2004Ozcan U. Cao Q. Yilmaz E. Lee A.H. Iwakoshi N.N. Ozdelen E. Tuncman G. Görgün C.Z. Glimcher L.H. Hotamisligil G.S. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.Science. 2004; 306: 457-461Crossref PubMed Scopus (2978) Google Scholar, Ozcan et al., 2006Ozcan U. Yilmaz E. Ozcan L. Furuhashi M. Vaillancourt E. Smith R.O. Görgün C.Z. Hotamisligil G.S. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.Science. 2006; 313: 1137-1140Crossref PubMed Scopus (1986) Google Scholar, Hotamisligil, 2010Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.Cell. 2010; 140: 900-917Abstract Full Text Full Text PDF PubMed Scopus (2090) Google Scholar). To this end, we searched for ER stress markers in cell cultures and in different animal models of AD. Using mature cultured hippocampal neurons, we found increased IRE1α-pSer724 in dendrites and cell bodies after exposure of neurons to AβOs for 3 hr (Figures 1A and 1B and S1A available online). Consistent with increased endonuclease activity of IRE1α upon phosphorylation, levels of spliced X box binding protein 1 (XBP1), a downstream effector of IRE1α recently proposed as a connection between UPR and insulin signaling (Park et al., 2010Park S.W. Zhou Y. Lee J. Lu A. Sun C. Chung J. Ueki K. Ozcan U. The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation.Nat. Med. 2010; 16: 429-437Crossref PubMed Scopus (226) Google Scholar, Winnay et al., 2010Winnay J.N. Boucher J. Mori M.A. Ueki K. Kahn C.R. A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response.Nat. Med. 2010; 16: 438-445Crossref PubMed Scopus (150) Google Scholar), were increased in oligomer-exposed neurons (Figure S1B). Further, AβOs increased dendritic and cell body levels of eIF2α-pSer51 (eIF2α-P) in hippocampal neurons (Figures 1C, 1D, and S1C). We also detected increased neuronal levels of 78 kDa glucose-regulated protein (GRP78) (also known as binding immunoglobulin protein, Bip), an ER chaperone that is part of the stress response program and is upregulated in AD brains (Hoozemans et al., 2005Hoozemans J.J.M. Veerhuis R. Van Haastert E.S. Rozemuller J.M. Baas F. Eikelenboom P. Scheper W. The unfolded protein response is activated in Alzheimer’s disease.Acta Neuropathol. 2005; 110: 165-172Crossref PubMed Scopus (431) Google Scholar), in oligomer-exposed neurons (Figure S1D). Prolonged ER stress is known to trigger apoptosis mediated by C/EBP homologous protein (CHOP; also known as growth arrest- and DNA damage-inducible gene 153, GADD153) (Lai et al., 2007Lai E. Teodoro T. Volchuk A. Endoplasmic reticulum stress: signaling the unfolded protein response.Physiology (Bethesda). 2007; 22: 193-201Crossref PubMed Scopus (397) Google Scholar). In line with the results described above, CHOP mRNA levels were increased in neurons exposed to AβOs for 24 hr (Figure S1E). Next, we looked for eIF2α-P in the brains of APPSwe,PS1ΔE9 (APP/PS1) mice. These mice harbor transgenes for human amyloid precursor protein (APP) bearing the Swedish mutation and a deletion mutant form of presenilin 1 (PS1) and present increased Aβ production and cognitive deficits (Jankowsky et al., 2001Jankowsky J.L. Slunt H.H. Ratovitski T. Jenkins N.A. Copeland N.G. Borchelt D.R. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies.Biomol. Eng. 2001; 17: 157-165Crossref PubMed Scopus (610) Google Scholar). APP/PS1 mice displayed increased hippocampal levels of eIF2α-P compared to wild-type animals (Figure 1E). Four kinases (PKR-like endoplasmic reticulum kinase [PERK], double-stranded RNA-dependent protein kinase [PKR], general control nonrepressed kinase 2 [GCN2], and heme-regulated inhibitor [HRI]) have been reported to phosphorylate eIF2α under stress conditions (Gkogkas et al., 2010Gkogkas C. Sonenberg N. Costa-Mattioli M. Translational control mechanisms in long-lasting synaptic plasticity and memory.J. Biol. Chem. 2010; 285: 31913-31917Crossref PubMed Scopus (55) Google Scholar). PERK and PKR are the main eIF2α kinases in response to ER stress and inflammation, respectively (Raven and Koromilas, 2008Raven J.F. Koromilas A.E. PERK and PKR: old kinases learn new tricks.Cell Cycle. 2008; 7: 1146-1150Crossref PubMed Scopus (84) Google Scholar). We therefore examined the roles of both kinases in oligomer-induced eIF2α-P in neurons. In hippocampal neuronal cultures, the distribution of activated PERK (PERK-pThr981) was mainly restricted to cell bodies, and its levels were not altered by exposure to AβOs for 3 hr (Figures S2A and S2B). In contrast, PKR was activated by exposure to AβOs in neuronal cultures (Figures 1F and 1G). AβOs are known to selectively target a subset of neurons in hippocampal cultures (Lacor et al., 2007Lacor P.N. Buniel M.C. Furlow P.W. Clemente A.S. Velasco P.T. Wood M. Viola K.L. Klein W.L. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease.J. Neurosci. 2007; 27: 796-807Crossref PubMed Scopus (994) Google Scholar). Importantly, elevated phospho-PKR levels were found independent of whether or not neurons exhibited oligomers bound to their dendrites (Figure 1H). This indicates that PKR phosphorylation is not triggered by direct binding of oligomers to individual neurons, but rather is instigated by soluble factors released to the medium upon exposure of cultures to AβOs. To establish the in vivo relevance of these findings, we analyzed levels of active PKR and PERK in the brains of APP/PS1 transgenic mice. Increased phosphorylation of PKR, but not of PERK, was detected in hippocampi of APP/PS1 mice compared to wild-type controls (Figures 1I and S2C). Consistent with the role of PKR in AβO-dependent eIF2α-P, pharmacological inhibition of PKR completely blocked oligomer-induced eIF2α-P as well as IRE1α-pSer724 (Figures 1J and 1K) in cultured hippocampal neurons. We further extended our investigation to the brains of monkeys that received i.c.v. infusions of AβOs. In monkeys, AβOs promoted eIF2α-P (Figures 1L, 1M, S1F, and S1G) and PKR activation in the hippocampus and entorhinal cortex (Figures 1N, 1O, S1H, and S1I). In metabolic disorders, ER stress has been linked to insulin resistance and proinflammatory TNF-α signaling (Ozcan et al., 2006Ozcan U. Yilmaz E. Ozcan L. Furuhashi M. Vaillancourt E. Smith R.O. Görgün C.Z. Hotamisligil G.S. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.Science. 2006; 313: 1137-1140Crossref PubMed Scopus (1986) Google Scholar, Steinberg et al., 2006Steinberg G.R. Michell B.J. van Denderen B.J.W. Watt M.J. Carey A.L. Fam B.C. Andrikopoulos S. Proietto J. Görgün C.Z. Carling D. et al.Tumor necrosis factor α-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling.Cell Metab. 2006; 4: 465-474Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar). To determine whether TNF-α activation was involved in AβO-induced phospho-PKR and eIF2α-P in hippocampal neurons, we first treated cultures with infliximab, a TNF-α neutralizing monoclonal antibody. Infliximab suppressed both PKR activation and eIF2α-P triggered by oligomers (Figures 2A–2E). SP600125, a specific JNK inhibitor, also blocked eIF2α-P in neuronal cultures (Figures 2D and 2E), in line with recent studies that have implicated the JNK pathway in AβO-induced IRS-1 inhibition (Ma et al., 2009Ma Q.L. Yang F. Rosario E.R. Ubeda O.J. Beech W. Gant D.J. Chen P.P. Hudspeth B. Chen C. Zhao Y. et al.β-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin.J. Neurosci. 2009; 29: 9078-9089Crossref PubMed Scopus (428) Google Scholar, Bomfim et al., 2012Bomfim T.R. Forny-Germano L. Sathler L.B. Brito-Moreira J. Houzel J.C. Decker H. Silverman M.A. Kazi H. Melo H.M. McClean P.L. et al.An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers.J. Clin. Invest. 2012; 122: 1339-1353Crossref PubMed Scopus (643) Google Scholar, De Felice, 2013De Felice F.G. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications.J. Clin. Invest. 2013; 123: 531-539Crossref PubMed Scopus (247) Google Scholar). It is notable that infliximab did not block oligomer binding to neurons (Figures 2F and 2G), substantiating the notion that activation of TNF-α/PKR signaling is independent of direct binding of AβOs to individual neurons and is likely mediated by TNF-α secreted to the medium. Indeed, TNF-α levels were increased in the culture medium after exposure to oligomers (Figure 2H), consistent with our recent finding that TNF-α levels are increased in the brains of mice that received i.c.v infusions of oligomers (Ledo et al., 2013Ledo J.H. Azevedo E.P. Clarke J.R. Ribeiro F.C. Figueiredo C.P. Foguel D. De Felice F.G. Ferreira S.T. Amyloid-β oligomers link depressive-like behavior and cognitive deficits in mice.Mol. Psychiatry. 2013; 18: 1053-1054Crossref PubMed Scopus (116) Google Scholar). We next hypothesized that activation of proinflammatory TNF-α signaling might be connected to AβO-induced memory impairment. Supporting this hypothesis, infliximab prevented memory impairment triggered by AβOs in mice (Figure 3A). We next injected oligomers i.c.v. in TNFR1−/− mice. Significantly, AβOs caused memory deficits in wild-type (WT) mice, but not in TNFR1−/− mice (Figures 3B, 3C, and S3). These results implicate TNF-α signaling in the mechanism underlying memory impairment induced by AβOs in mice. Interestingly, AβOs triggered phosphorylation of PKR and eIF2α in the hippocampus of WT mice, but not in TNFR1−/− mice (Figures 3D and 3E), establishing that activation of TNF-α receptors lies upstream of PKR and eIF2α-P in vivo. Synapse loss has been proposed to be the best pathological correlate of the extent of dementia in AD (Terry et al., 1991Terry R.D. Masliah E. Salmon D.P. Butters N. DeTeresa R. Hill R. Hansen L.A. Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment.Ann. Neurol. 1991; 30: 572-580Crossref PubMed Scopus (3394) Google Scholar), and AD brains present reduced levels of synaptophysin and PSD-95, pre- and postsynaptic markers, respectively (Terry et al., 1991Terry R.D. Masliah E. Salmon D.P. Butters N. DeTeresa R. Hill R. Hansen L.A. Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment.Ann. Neurol. 1991; 30: 572-580Crossref PubMed Scopus (3394) Google Scholar). AβOs have been shown to reduce the levels of synaptophysin or PSD-95 in neuronal cultures, in the brains of mice receiving i.c.v. infusions of oligomers, and in ex vivo human cortical slices (Sebollela et al., 2012Sebollela A. Freitas-Correa L. Oliveira F.F. Paula-Lima A.C. Saraiva L.M. Martins S.M. Mota L.D. Torres C. Alves-Leon S. de Souza J.M. et al.Amyloid-β oligomers induce differential gene expression in adult human brain slices.J. Biol. Chem. 2012; 287: 7436-7445Crossref PubMed Scopus (67) Google Scholar, Figueiredo et al., 2013Figueiredo C.P. Clarke J.R. Ledo J.H. Ribeiro F.C. Costa C.V. Melo H.M. Mota-Sales A.P. Saraiva L.M. Klein W.L. Sebollela A. et al.Memantine rescues transient cognitive impairment caused by high-molecular-weight aβ oligomers but not the persistent impairment induced by low-molecular-weight oligomers.J. Neurosci. 2013; 33: 9626-9634Crossref PubMed Scopus (130) Google Scholar). Supporting the notion that synaptic deterioration underlies TNF-α-dependent memory impairment induced by AβOs, levels of synaptophysin and PSD-95 were decreased in hippocampi of WT, but not of TNFR1−/−, mice i.c.v. injected with AβOs (Figure 3F). To determine the role of PKR in AβO-induced cognitive impairment, we investigated the effect of AβOs in PKR−/− mice. Importantly, we found that AβOs induced hippocampal eIF2α-P and cognitive deficits in WT mice, but not in PKR−/− mice (Figures 3G–3I). These results demonstrate that PKR, recently implicated in metabolic stress and impaired insulin signaling in diabetes (Nakamura et al., 2010Nakamura T. Furuhashi M. Li P. Cao H. Tuncman G. Sonenberg N. Gorgun C.Z. Hotamisligil G.S. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis.Cell. 2010; 140: 338-348Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar), is a key mediator of neuronal eIF2α-P and memory impairment induced by AβOs. To further examine the impact of PKR activation on synapses, we exposed hippocampal cultures to AβOs in the absence or presence of a PKR inhibitor. After 24 hr, we evaluated synapse density by determining immunoreactivities of synaptophysin and PSD-95 and their colocalization at synapses. Results showed that inhibition of PKR attenuated synapse loss induced by AβOs (Figures 3J–3M) and suggest that loss of synaptic proteins underlies the deleterious effects of PKR on memory. Based on the findings described above, we hypothesized that elevated eIF2α-P in the brain might be linked to memory impairment triggered by AβOs. To explore the connection between eIF2α-P and memory, we performed i.p. injections of salubrinal (an inhibitor of GADD34, a phosphatase that preferentially dephosphorylates eIF2α) to increase eIF2α-P levels in the hippocampi of adult Swiss mice. Animals that received salubrinal presented memory impairment in the novel object recognition task (Figure 4A) and significantly lower hippocampal levels of PSD-95 and synaptophysin (Figures 4B–4D). We also found decreased levels of synaptophysin and PSD-95, as well as decreased synapse density, in salubrinal-exposed hippocampal cultures (Figures 4E–4H). Control experiments indicated that, as expected, salubrinal promoted eIF2α-P in hippocampal neurons in culture (Figures S4A and S4B) and in the brains of injected mice (Figure S4C). These results show that eIF2α-P is sufficient to cause memory impairment and synapse loss in mice. Additional support to the notion that eIF2α-P and, more generally, ER stress cause memory impairment came from the observation that thapsigargin, a classical inducer of ER stress that triggers eIF2α-P in neurons (Figures S5A and S5B), caused brain eIF2α-P and memory impairment when injected i.c.v. in mice (Figures S5C and S5D). 4-phenylbutyrate (4-PBA), a chemical chaperone known to alleviate ER stress, prevented memory loss (Figure S5D). 4-PBA further blocked memory impairment caused by i.c.v. injection of AβOs in mice (Figure S5E), implicating ER stress in the impact of AβOs on memory. We recently reported that TNF-α and PKR mediate IRS-1 inhibition in cultured hippocampal neurons (Bomfim et al., 2012Bomfim T.R. Forny-Germano L. Sathler L.B. Brito-Moreira J. Houzel J.C. Decker H. Silverman M.A. Kazi H. Melo H.M. McClean P.L. et al.An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers.J. Clin. Invest. 2012; 122: 1339-1353Crossref PubMed Scopus (643) Google Scholar). Establishing that proinflammatory TNF-α mediates oligomer-induced IRS-1 inhibition in vivo, AβOs triggered IRS-1pSer636 in the hippocampus of WT mice, but not in TNFR1−/− mice (Figure 5A). We also examined IRS-1pSer levels in the brains of PKR−/− mice. Possibly reflecting different patterns of activation of IRS-1 in mice of different genetic backgrounds (Xu et al., 2013Xu J. Gontier G. Chaker Z. Lacube P. Dupont J. Holzenberger M. Longevity effect of IGF-1R(+/-) mutation depends on genetic background-specific receptor activation.Aging Cell. 2013; (Published online July 30, 2013)https://doi.org/10.1111/acel.12145Crossref Scopus (75) Google Scholar), we did not detect increased IRS-1pSer levels induced by AβOs in WT 129/SvEv mice. Interestingly, however, lower IRS-1pSer levels were found in PKR−/− mice than in WT mice, demonstrating that suppression of PKR per se attenuates IRS-1 inhibition (Figure 5B). Because ER stress and eIF2α-P are linked to insulin resistance in peripheral tissues (Ozcan et al., 2004Ozcan U. Cao Q. Yilmaz E. Lee A.H. Iwakoshi N.N. Ozdelen E. Tuncman G. Görgün C.Z. Glimcher L.H. Hotamisligil G.S. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.Science. 2004; 306: 457-461Crossref PubMed Scopus (2978) Google Scholar, Birkenfeld et al., 2011Birkenfeld A.L. Lee H.Y. Majumdar S. Jurczak M.J. Camporez J.P. Jornayvaz F.R. Frederick D.W. Guigni B. Kahn M. Zhang D. et al.Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism.J. Biol. Chem. 2011; 286: 36163-36170Cro" @default.
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• W2034632760 title "TNF-α Mediates PKR-Dependent Memory Impairment and Brain IRS-1 Inhibition Induced by Alzheimer’s β-Amyloid Oligomers in Mice and Monkeys" @default.
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