The role of autophagy in age-related neurodegeneration.
ABSTRACT Most age-related neurodegenerative diseases are characterized by accumulation of aberrant protein aggregates in affected brain regions. In many cases, these proteinaceous deposits are composed of ubiquitin conjugates, suggesting a failure in the clearance of proteins targeted for degradation. The 2 principal routes of intracellular protein catabolism are the ubiquitin proteasome system and the autophagy-lysosome system (autophagy). Both of these degradation pathways have been implicated as playing important roles in the pathogenesis of neurodegenerative disease. Here we describe autophagy and review the evidence suggesting that impairment of autophagy contributes to the initiation or progression of age-related neurodegeneration. We also review recent evidence indicating that autophagy may be exploited to remove toxic protein species, suggesting novel strategies for therapeutic intervention for a class of diseases for which no effective treatments presently exist.
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ABSTRACT: Age-related neurodegenerative diseases have been associated with chronic neuroinflammation and microglia activation. However, cumulative evidence supports that inflammation only occurs at an early stage once microglia change the endogenous characteristics with aging and switch to irresponsive/senescent and dystrophic phenotypes with disease progression. Thus, it will be important to have the means to assess the role of reactive and aged microglia when studying advanced brain neurodegeneration processes and age-associated related disorders. Yet, most studies are done with microglia from neonates since there are no adequate means to isolate degenerating microglia for experimentation. Indeed, only a few studies report microglia isolation from aged animals, using either short-term cultures or high concentrations of mitogens in the medium, which trigger microglia reactivity. The purpose of this study was to develop an experimental process to naturally age microglia after isolation from neonatal mice and to characterize the cultured cells at 2 days in vitro (DIV), 10 DIV, and 16 DIV. We found that 2 DIV (young) microglia had predominant amoeboid morphology and markers of stressed/reactive phenotype. In contrast, 16 DIV (aged) microglia evidenced ramified morphology and increased matrix metalloproteinase (MMP)-2 activation, as well as reduced MMP-9, glutamate release and nuclear factor kappa-B activation, in parallel with decreased expression of Toll-like receptor (TLR)-2 and TLR-4, capacity to migrate and phagocytose. These findings together with the reduced expression of microRNA (miR)-124, and miR-155, decreased autophagy, enhanced senescence associated beta-galactosidase activity and elevated miR-146a expression, are suggestive that 16 DIV cells mainly correspond to irresponsive/senescent microglia. Data indicate that the model represent an opportunity to understand and control microglial aging, as well as to explore strategies to recover microglia surveillance function.Frontiers in Cellular Neuroscience 06/2014; 8:152. DOI:10.3389/fncel.2014.00152 · 4.18 Impact Factor
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ABSTRACT: Despite the progress of the past two decades, the cause of Alzheimer's disease (AD) and effective treatments against it remain elusive. The hypothesis that amyloid-β (Aβ) peptides are the primary causative agents of AD retains significant support among researchers. Nonetheless, a growing body of evidence shows that Aβ peptides are unlikely to be the sole factor in AD etiology. Evidence that Aβ/amyloid-independent factors, including the actions of AD-related genes, also contribute significantly to AD pathogenesis was presented in a symposium at the 2010 Annual Meeting of the Society for Neuroscience. Here we summarize the studies showing how amyloid-independent mechanisms cause defective endo-lysosomal trafficking, altered intracellular signaling cascades, or impaired neurotransmitter release and contribute to synaptic dysfunction and/or neurodegeneration, leading to dementia in AD. A view of AD pathogenesis that encompasses both the amyloid-dependent and -independent mechanisms will help fill the gaps in our knowledge and reconcile the findings that cannot be explained solely by the amyloid hypothesis.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2010; 30(45):14946-54. DOI:10.1523/JNEUROSCI.4305-10.2010 · 6.75 Impact Factor
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ABSTRACT: Substantial progress has been made throughout the last decades in the elucidation of the key players and mechanisms responsible for Ca2+ signal generation in both excitable and non-excitable cells. Importantly, these studies led also to the recognition that a close correlation exists between the deregulation of cellular Ca2+ homeostasis and the development of several human pathologies, including neurodegenerative disease. Notwithstanding this advances, much less is certain about the targets and mechanisms by which compromised Ca2+ signaling exerts its effects on cell function and survival. Recently it has been proposed that deregulation of cellular energy metabolism and protein turnover (synthesis, folding and degradation) are also fundamental pathomechanisms of neurodegenerative disease, pointing to the pivotal role of autophagy, a major cellular pathway controlling metabolic homeostasis. Indeed, activation of autophagy has been shown to represent a highly successful strategy to restore normal neuronal function in a variety of models of neurodegenerative disease. Here we review recent advances in elucidating Ca2+ regulation of autophagy and will highlight its relationship to neurodegeneration.Cell calcium 02/2010; 47(2):112-21. DOI:10.1016/j.ceca.2009.12.013 · 4.21 Impact Factor