Amyloid-beta-Induced Mitochondrial Dysfunction Impairs the Autophagic Lysosomal Pathway in a Tubulin Dependent Pathway
Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal. Journal of Alzheimer's disease: JAD
(Impact Factor: 4.15).
06/2011; 26(3):565-81. DOI: 10.3233/JAD-2011-110423
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.
Available from: Paula I Moreira
- "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). "
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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 · 2.06 Impact Factor
Available from: Ana Catarina RG Fonseca
- "This was probably due to an increased accumulation of damaged proteins and organelles that were not efficiently degraded by macroautophagy. Aβ can be degraded by macroautophagy but this peptide can also be generated within endosomes and in autophagosomes when lysosomal degradation is compromised   . Despite the fact that Aβ 1–40 , thapsigargin and lactacystin did not significantly induce macroautophagy, autophagosome accumulation due to a decrease in their turnover can potentiate the formation of Aβ. "
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ABSTRACT: Abnormal accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer's disease (AD). In addition to neurotoxic effects, Aβ also damages brain endothelial cells (ECs) and may thus contribute to the degeneration of cerebral vasculature, which has been proposed as an early pathogenic event in the course of AD and is able to trigger and/or potentiate the neurodegenerative process and cognitive decline. However, the mechanisms underlying Aβ-induced endothelial dysfunction are not completely understood. Here we hypothesized that Aβ impairs protein quality control mechanisms both in the secretory pathway and in the cytosol in brain ECs, leading cells to death. In rat brain RBE4 cells, we demonstrated that Aβ1-40 induces the failure of the ER stress-adaptive unfolded protein response (UPR), deregulates the ubiquitin-proteasome system (UPS) decreasing overall proteasome activity with accumulation of ubiquitinated proteins and impairs the autophagic protein degradation pathway due to failure in the autophagic flux, which culminates in cell demise. In conclusion, Aβ deregulates proteostasis in brain ECs and, as a consequence, these cells die by apoptosis.
Biochimica et Biophysica Acta 02/2014; 1843(6). DOI:10.1016/j.bbamcr.2014.02.016 · 4.66 Impact Factor
Available from: Saar Oz
- "The neuroprotective effect of NAP paralleled protection against apoptosis (cytochrome-c release), protection against caspase 3 activation  and MT breakdown protection , . Recent studies suggested that MT polymerization re-establishment by protective paclitaxel concentrations reduced amyloid β oligomers , which in turn have been associated with the formation of hyperphosphorylated tau . Thus, protection of MT polymerization by NAP has far reaching mechanistic consequences on protection in Alzheimer’s disease and related tauopathies. "
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ABSTRACT: Microtubules (MTs), key cytoskeletal elements in living cells, are critical for axonal transport, synaptic transmission, and maintenance of neuronal morphology. NAP (NAPVSIPQ) is a neuroprotective peptide derived from the essential activity-dependent neuroprotective protein (ADNP). In Alzheimer's disease models, NAP protects against tauopathy and cognitive decline. Here, we show that NAP treatment significantly affected the alpha tubulin tyrosination cycle in the neuronal differentiation model, rat pheochromocytoma (PC12) and in rat cortical astrocytes. The effect on tubulin tyrosination/detyrosination was coupled to increased MT network area (measured in PC12 cells), which is directly related to neurite outgrowth. Tubulin beta3, a marker for neurite outgrowth/neuronal differentiation significantly increased after NAP treatment. In rat cortical neurons, NAP doubled the area of dynamic MT invasion (Tyr-tubulin) into the neuronal growth cone periphery. NAP was previously shown to protect against zinc-induced MT/neurite destruction and neuronal death, here, in PC12 cells, NAP treatment reversed zinc-decreased tau-tubulin-MT interaction and protected against death. NAP effects on the MT pool, coupled with increased tau engagement on compromised MTs imply an important role in neuronal plasticity, protecting against free tau accumulation leading to tauopathy. With tauopathy representing a major pathological hallmark in Alzheimer's disease and related disorders, the current findings provide a mechanistic basis for further development. NAP (davunetide) is in phase 2/3 clinical trial in progressive supranuclear palsy, a disease presenting MT deficiency and tau pathology.
PLoS ONE 12/2012; 7(12):e51458. DOI:10.1371/journal.pone.0051458 · 3.23 Impact Factor
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