, 2003). Additional information on DNA constructs, Y2H analysis, GST pull-downs, immunofluorescence microscopy, immunoprecipitation,

antibodies, and statistical analysis is provided in Supplemental Experimental Procedures. We thank X. Zhu and N. Tsai for expert technical assistance, D. Arnold, G. Bloom, F. Brodsky, E. Gundelfinger, K. Howell, P. Kammermeier, J. Lippincott-Schwartz, G. Mardones, M. Nonet, M. Parsons, T. Ryan, L. Traub, S. Vicini, and B. Winckler for kind gifts of reagents, and J. Hurley for helpful discussions and critical reading of the manuscript. This work was funded by Venetoclax molecular weight the Intramural Program of NICHD, NIH. “
“Aβ peptide accumulation is a hallmark of Alzheimer’s disease (AD), being released from neurons via extracellular and subsequent intramembrane cleavage reactions of the amyloid precursor protein (APP) (Tanzi and Bertram, 2005). Recent findings suggest that soluble oligomeric are the pathogenic forms, eliciting neurotoxic effects that culminate in synaptic dysfunction and neuronal loss (Haass and Selkoe, 2007). Discovery of Prp and EphB2 as receptors for oligomeric Aβ42 (Cissé et al., 2011; Laurén et al., 2009) provides support for the view that oligomeric Aβ peptides could function as neurotoxic ligands, initiating diverse cellular signaling events that range widely, including inflammation, mitochondrial

dysfunction, oxidative stress, apoptosis/autophagy, intracellular calcium imbalance, and a block in LTP (Koo and Kopan, 2004), any of which could contribute to AD pathology. Akt inhibitor Oxymatrine The mechanism by which oligomeric Aβ peptides elicit such diverse cellular

outcomes, however, has remained elusive. Here, we report that oligomeric Aβ42 exerts such diverse effects in part by inducing a translational block, which is accompanied by ER stress as indicated by increased phosphorylation of Eif2α in hippocampal neurons. Increased Eif2α phosphorylation was reported to inhibit the late phase of LTP and memory acquisition (Costa-Mattioli et al., 2007, 2009). Once induced, ER stress activates Unfolded Protein Response (UPR), inducing widespread secondary reactions, some of which include changes in inflammatory responses as well as cell survival programs (Ron and Walter, 2007), the often reported phenotypes in AD. As part of UPR, ER stress activates the JNK pathway (Urano et al., 2000). JNK proteins, especially JNK3, a brain-specific JNK isoform, have been reported to play roles under neurodegenerative conditions, such as Parkinson’s disease: deletion of JNK3 in combination with JNK2 prevented loss of dopaminergic neurons after MPTP administration ( Hunot et al., 2004). Deleting JNK3 also resulted in a significant increase in neuronal and oliogodendrocyte survival after traumatic injuries in the CNS ( Beffert et al., 2006; Li et al., 2007).