The creation of autophagy-specific knockout mice in 2006 and the observation of their neurodegenerative phenotype brought autophagy to the attention of the broader neuroscientific community.21,22 The accumulation of autophagosomes and nondegraded material in neurons of brains in patients with AD and the presence of APP-processing secretases in autophagosomes had already indicated that autophagy participates in the turnover of APP and its metabolites and that it might be deregulated in AD.23- 25 Additionally, changes in autophagy and endosomal sorting-related messenger RNAs had been reported in brain tissues of patients with AD.26 A study from our laboratory then identified Beclin 1, a protein involved in the initiation and execution of autophagy, to be reduced in AD brain tissue, linking the disease to an autophagy defect (Figure 2A).27 Accordingly, APP-transgenic mice with a heterozygous deletion of Beclin 1 have an increase in Aβ plaque deposition, neuronal loss, and the accumulation of abnormal lysosomes containing electron-dense material.27 These findings indicate that autophagy plays a central role in APP transport and metabolism, a hypothesis that is further supported by new cell culture data from our laboratory: APP and APP metabolites are degraded via the autophagy pathway, and Beclin 1 reduction increases APP, APP C-terminal fragment, and Aβ accumulation in cell culture.28 Interestingly, APP overexpression, both in cells and in mice, causes no detectable change in Beclin 1 levels.27,28 This suggests that disturbances in autophagy precede the pathological disruption of APP processing. Beclin 1 had initially been identified as a tumor suppressor gene29 and is now at the center of research aiming to understand the complex molecular events surrounding autophagy initiation and execution. A series of landmark studies published in the last 3 years showed that Beclin 1 is at the core of a large protein complex that regulates multiple aspects of autophagy, depending on its subunit composition (Figure 2B).30- 36 The question is, to what extent is autophagy involved in the development or prevention of neurotoxic events, and can modulating autophagy cause or rescue neurodegeneration? Autophagy appears impaired in presenilin 1/APP mice and contributes to neuronal apoptosis,24,37 while it is constitutively active in healthy neurons.38 In addition, Aβ1-42 has been reported to directly impair the autophagosomal-lysosomal system in flies,39 and Aβ oligomers interfere with mTOR signaling.40 On the other hand, activation of autophagy or overexpression of Beclin 1 can prevent neuronal cell death and promote clearance of toxic protein aggregates.41- 43 These data suggest a model where basal autophagy plays an important role in neuronal protein housekeeping and vesicular turnover. Disruption of autophagy would lead to an accumulation of abnormal subcellular vesicles (endosomes, lysosomes, multivesicular bodies, autophagosomes), which are part of the native APP trafficking system and present the right microenvironment to produce potentially toxic APP metabolites. Increasing levels of these toxic species, including Aβ, could then contribute further to an escalating disruption of the autophagosomal system and ultimately to cell death. A rescue of autophagy levels or a mild overactivation appears to have beneficial effects, while extreme autophagy activation can lead to cell death by itself.