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Background: Emerging evidence points on the role of APP C-terminal peptides in the onset of neurodegeneration and Alzheimer's disease (AD) (Simon et al., 2009). Transgenic mice overexpressing APP intracellular domain (AICD) show AD-like pathological features, apparently in a betaamyloid-independent manner (Ghosal et al., 2009) and AICD and other C-terminal peptides are found in AD patient's brains (Russo et al., 2001). New vivo insights on the role of APP intracellular domain in APP physiology and function came from APP knock-in mice, in which Y 682 is replaced by a glycine, G (APPY682G) (Barbagallo et al., 2010). When this point mutation is introduced into an APLP2 -/-background (von Koch et al., 1997), APP Y682G/APLP2 -/-mutant mice exhibit neuromuscular synapse deficits and early lethality similar to APP/APLP2 double KO mice (Barbagallo et al., 2011), suggesting an essential role of the Y 682 ENPTY 687 domain in development. Methods: Neuromotor performances have been evaluated by Treadmill and Rotarod tests AA acquisition, Spatial working memory, NOR and Open field have been used to evaluate Cognitive and learning abilities. Spine densities as well as electrophysiological and biochemical studies were performed to support and explain results from behavioral analysis. Results: Our recent findings indicate that mutation on Y 682 residue causes a premature aging-dependent decline in learning, cognitive and neuromuscular performances in mice. 5 months old APP Y682G mice show impaired physical resistance in treadmill tests that appears consistently associated to neuromuscular activity deficit and synaptic failure. A strong early loss in dendritic spine density is detectable in hippocampus from 2 month-aged APP Y682G mice suggesting that synaptic impairment precedes behavioral deficits. In addition, 7 month-aged APP Y682G mice display a strong cholinergic neurodegeneration and a reduction in neurotrophic receptor expression and activity (TrkA) (Matrone et al 2011;2012). Conclusions: The profound deficits caused by the Y 682 mutation underscore the biological importance of such residue in APP physiology and function. Remarkably, the finding that AID overexpression is not toxic per se in mice and does not reproduce AD features in vivo (Giliberto et al., 2010), suggests that other more complicated and not well-understood mechanisms might regulate APP activity in vivo and indicates Y682 as new possible candidate in such events.Background: N-terminally truncated and pyroglutamated (pGlu, pE) betaamyloid peptides are abundant in human sporadic and inherited Alzheimer's disease (AD). Formation of pE at the N-terminus confers resistance against protease cleavage and has been shown to increase beta-amyloid aggregation propensity and toxicity. In contrast to human AD, however, most of the common hAPP-transgenic mouse models show only low levels of pE3-beta-amyloid, which is detectable only at later age. On our quest to develop approaches that target pE-modified beta-amyloid as treatments for AD, we generated double transgenic...

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