Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2010; 107(32):14164-9. DOI: 10.1073/pnas.1009485107
Source: PubMed


Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid beta peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by Abeta is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional up-regulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death.

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Available from: Marta Lipinski
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    • "Autophagy is an important degradation process, which can remove the damaged mitochondria and aggregated proteins [8] [9]. Various studies found that the expression of autophagy-related genes and the efficiency of autophagic process decline with aging [10]. The inhibition of autophagy could accelerate premature aging, whereas the enhancement of autophagy might delay aging and extend lifespan [11]. "
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    • "This is important, for example, during age-related macular degeneration (AMD), where increased autophagy and the release of exosomes may contribute to the formation of drusen (53). Autophagy appears to decline with age, and several key players in the autophagic pathway (ATG5 and ATG7) show decreased expression in the brains of aging individuals (54). In addition, a decrease in LAMP-2A is the responsible for diminished CMA activity during aging (55). "
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    ABSTRACT: Conditions resulting from loss of cellular homeostasis, including oxidative stress, inflamma-tion, protein aggregation, endoplasmic reticulum stress, metabolic stress, and perturbation of mitochondrial function, are common to many pathological disorders and contribute to aging. Cells face these stress situations by engaging quality control mechanisms aimed to restore cellular homeostasis and preserve cell viability. Among them, the autophagy-lysosomal pathway mediates the specific degradation of damaged proteins and organelles, and its proper function is related to cellular protection and increased life span in many model organisms. Besides autophagy, increasing evidence underscores a role for exosomes in the selective secretion of harmful/damaged proteins and RNAs and thus in the mainte-nance of cellular fitness. In this perspective article, we discuss the emerging function of exosomes as a means of alleviating intracellular stress conditions, and how secretion of harmful or unwanted material in exosomes, in coordination with the autophagy-lysosomal pathway, is essential to preserve intracellular protein and RNA homeostasis. Finally, we provide an overview about the consequences of the spreading of the exosome content in physiological and pathological situations, and suggest putative therapeutic strategies for these exosome-mediated alterations.
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    • "The progressive decline of the autophagic activity and the reduced expression of different autophagy-regulating genes represent some of the hallmarks of the aging process (Lionaki et al., 2013; Lopez-Otin et al., 2013; Rubinsztein et al., 2011). Genome-wide analysis revealed autophagy decline in normal human brain aging (Lipinski et al., 2010), and administration of rapamycin (the mTOR inhibitor) extended lifespan in mice (Anisimov et al., 2011; Harrison et al., 2009). Consistently , studies from invertebrate model organisms, have clearly demonstrated that genetic (e.g. "
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