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.
"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). "
[Show abstract][Hide abstract] 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
"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. "
[Show abstract][Hide abstract] 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
"To examine the role of Aβ in reducing acetylated α-tubulin, primary hippocampal neurons were characterized. Consistent with previous studies , , the level of acetylated α-tubulin was significantly decreased by the Aβ treatment (Fig. 2), as shown by Western blot analysis (Fig. 2A and 2B, *p<0.05, ***P<0.001) "
[Show abstract][Hide abstract] ABSTRACT: Even though the disruption of axonal transport is an important pathophysiological factor in neurodegenerative diseases including Alzheimer's disease (AD), the relationship between disruption of axonal transport and pathogenesis of AD is poorly understood. Considering that α-tubulin acetylation is an important factor in axonal transport and that Aβ impairs mitochondrial axonal transport, we manipulated the level of α-tubulin acetylation in hippocampal neurons with Aβ cultured in a microfluidic system and examined its effect on mitochondrial axonal transport. We found that inhibiting histone deacetylase 6 (HDAC6), which deacetylates α-tubulin, significantly restored the velocity and motility of the mitochondria in both anterograde and retrograde axonal transports, which would be otherwise compromised by Aβ. The inhibition of HDAC6 also recovered the length of the mitochondria that had been shortened by Aβ to a normal level. These results suggest that the inhibition of HDAC6 significantly rescues hippocampal neurons from Aβ-induced impairment of mitochondrial axonal transport as well as mitochondrial length. The results presented in this paper identify HDAC6 as an important regulator of mitochondrial transport as well as elongation and, thus, a potential target whose pharmacological inhibition contributes to improving mitochondrial dynamics in Aβ treated neurons.
PLoS ONE 08/2012; 7(8):e42983. DOI:10.1371/journal.pone.0042983 · 3.23 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.