Amyloid-beta-Induced Mitochondrial Dysfunction Impairs the Autophagic Lysosomal Pathway in a Tubulin Dependent Pathway
ABSTRACT Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain and peripheral tissues. Amyloid-β (Aβ) peptides are known to interact with several proteins inside the mitochondria, leading to mitochondrial dysfunction. Recent studies have provided substantial evidence that mitochondria serve as direct targets for Aβ-mediated neuronal toxicity. The observations that Aβ progressively accumulates in cortical mitochondria from AD patients and transgenic AD type mouse models suggest the role of mitochondrial Aβ in the pathogenesis or development of AD. Herein, we studied the downstream signaling pathways induced by Aβ-mediated mitochondrial metabolism alterations and its consequences on cellular fate. We found that Aβ peptides induced an increase in NAD+levels and a decrease in ATP levels, which was related with decreases in acetylated tubulin levels and tau hyperphosphorylation. As a result of microtubule disruption, alterations in macroautophagy, like a decrease in autophagossome degradation and altered cellular distribution of LC3B, were found. Taxol, a microtubule stabilizer drug, was able to restore microtubule network and to prevent cell death induced by Aβ peptides. Our data shows for the first time that mitochondrial and cytosolic Aβ oligomers were significantly reduced upon microtubule dynamics re-establishment. These observations point out that an intervention at a microtubule level may be effective as a disease modifying therapy.
- SourceAvailable from: Paula I Moreira
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- "Mechanistically, Ab was proposed to disrupt mitochondrial metabolism, compromising mitochondrial network dynamics and consequent Ab clearance by the autophagic– lysosomal pathway, generating a vicious cycle. Meanwhile, the reestablishment of a microtubule network with taxol is able to prevent abnormal autophagic flux and Ab neurotoxicity (Silva et al., 2011). Overall, AVs accumulated in dystrophic neurites represent major intracellular sites of Ab generation, where autophagy regulates AbPP turnover and stimulates g-secretase activity and Ab clearance (Yu et al., 2004, 2005; Mizushima , 2005). "
ABSTRACT: Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Given its key role as a cellular quality control mechanism, autophagy is now a focus of intense scrutiny in Alzheimer's disease (AD). The hallmarks of this devastating neurodegenerative disease are the accumulation of misfolded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein and neuronal loss, which are accompanied by mitochondrial dysfunction and endoplasmic reticulum (ER) stress, suggesting that faulty autophagy is a contributing factor to AD pathology. Indeed, the AD brain is characterized by a massive accumulation of autophagic vacuoles within large swellings along dystrophic neurites and defects at different steps of the autophagic-lysosomal pathway. In this sense, this review provides an overview on the role of autophagy on Aβ metabolism, tau processing and clearance, and the contribution of ER-phagy and mitophagy to AD pathology. From a therapeutic perspective, this review also intends to clarify whether, when, and how autophagy can be targeted to efficaciously counteract AD-related symptomatic and neuropathological features.DNA and Cell Biology 02/2015; 34(4). DOI:10.1089/dna.2014.2757 · 1.99 Impact Factor
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- "An increased autophagic degradation of mitochondria in AD brain was also observed  . Mitochondrial dysfunction induced by A␤ impaired the autophagylysosome pathway in a tubulin-dependent manner . Small enhancers of autophagy decreased the levels of A␤ and the A␤PP derived fragment A␤PP-CTF via Atg5-dependent autophagy pathway . "
ABSTRACT: An increasing number of studies have demonstrated a connection between Alzheimer's disease (AD) and diabetes, particularly type 2 diabetes (T2D). The risk for developing T2D and AD increases exponentially with age and having T2D increases the risk of developing AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. This review critically discusses the involvement of mitochondrial abnormalities and oxidative stress in AD and diabetes highlighting the similarities between both pathologies. The impact of insulin resistance/insulin signaling impairment in AD pathogenesis will be also debated. A better understanding of the key mechanisms underlying the interaction between AD and diabetes is needed for the design of effective preventive and therapeutic strategies.Journal of Alzheimer's disease: JAD 01/2012; 30 Suppl 2:S199-215. DOI:10.3233/JAD-2011-111127 · 4.15 Impact Factor
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- "Recently, Silva and co-workers demonstrated that in SH-SY5Y cells exposed to Aβ 1–42 , the resultant mitochondrial dysfunction perturbs AV transport via a microtubule-dependent mechanism(Silva et al., 2011a). Taxol prevents Aβ 1–42 -induced disorganization of the tubulin cytoskeleton, which secondarily reduces both cytosolic and mitochondrial Aβ content by enhancing ALP function. "
ABSTRACT: Mitochondria from persons with Alzheimer's disease (AD) differ from those of age-matched control subjects. Differences in mitochondrial morphology and function are well documented, and are not brain-limited. Some of these differences are present during all stages of AD, and are even seen in individuals who are without AD symptoms and signs but who have an increased risk of developing AD. This chapter considers the status of mitochondria in AD subjects, the potential basis for AD subject mitochondrial perturbations, and the implications of these perturbations. Data from multiple lines of investigation, including epidemiologic, biochemical, molecular, and cytoplasmic hybrid studies, are reviewed. The possibility that mitochondria could potentially constitute a reasonable AD therapeutic target is discussed, as are several potential mitochondrial medicine treatment strategies.Advances in pharmacology (San Diego, Calif.) 01/2012; 64:83-126. DOI:10.1016/B978-0-12-394816-8.00003-9