, 2007). Although critical experiments are still needed to address whether T668P phosphorylation causes APP processing in vivo, our study provides additional support to the idea that T668P phosphorylation significantly contributes to APP processing in vivo. We provide compelling evidence that a translational block is a prominent feature in FAD mice and to some http://www.selleckchem.com/autophagy.html extent in human AD cases. Since oligomeric Aβ42 induced a translational block in hippocampal neurons in culture, it is highly likely that

oligomeric Aβ42 has a similar effect in vivo. Oligomeric Aβ42 is widely believed to be the central pathologic species that is responsible for inhibiting LTP and memory formation in vivo (Cleary et al., 2005; Walsh et al., 2002). Since inhibiting normal translational processes by disabling eif2α phosphorylation or deleting its kinase, GCN2, resulted in inhibition of LTP ( Costa-Mattioli

et al., 2005, 2007), it is tempting to speculate that such synaptotoxicity observed with oligomeric Aβ42 is likely to be due to its inhibitory effect on translation. Our data indicate that oligomeric Aβ42 inhibits translation in part by blocking the mTOR pathway. Dysregulation of the mTOR pathway or loss of energy balance has GSK2656157 chemical structure been identified as causative in normal aging as well as type 2-diabetes and obesity (Cohen et al., 2009; Demontis and Perrimon, 2010; Koo et al., 2005; Mair et al., 2011; Song et al., 2010). Our findings that widespread disruption of normal energy balance is prominent in FAD mice and to some extent in human AD cases suggest that in progressive diseases whose symptoms develop

over a long period time, chronic metabolic imbalance becomes a pervasive phenotype. Our data clearly illustrate that oligomeric Aβ42 perturbs energy homeostasis, as indicated by activation of AMPK, a kinase that responds to energy imbalance in the cell (Steinberg and Kemp, 2009). AMPK was shown to play a critical role in aging in yeast and C. elegans, although the loss of snf1p, the yeast homolog of AMPK, increased the life span ( Lin et al., 2001), while mutation in aak-2, the worm MRIP homolog of AMPK, decreased the life extension induced by stress ( Apfeld et al., 2004). Besides this apparent species-related difference in homolog roles, the role of AMPK itself in aging appears clear. It is of special interest in this regard that oligomeric Aβ42 activates AMPK, thereby inhibiting the mTOR pathway. Aβ peptides are normally produced and cleared rapidly in human brains ( Bateman et al., 2006). It is plausible that normal production of Aβ peptides contributes to the aging process in part by activating AMPK. AMPK activation was rapid but transient by oligomeric Aβ42, detectable at 10 min, but greatly reduced by 3 hr after Aβ42 addition. Although transiently activated, AMPK substrates Raptor and TSC2 remain phosphorylated up to 16 hr, providing an explanation for a prolonged translational inhibition.