Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis

Guglielmotto, Michela; Monteleone, Debora; Piras, Antonio; Valsecchi, Valeria; Tropiano, Marta; Ariano, Stefania; Fornaro, Michele; Vercelli, Alessandro; Puyal, Julien; Arancio, Ottavio; Tabaton, Massimo; Tamagno, Elena

doi:10.4161/auto.30001

Cited by 72 publications

(67 citation statements)

References 55 publications

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“…We previously showed that they increase receptor for advanced glycation end products (RAGE) expression (Piras et al ., 2014), BACE1 protein levels (Piccini et al ., 2012), and inhibit lysosomal activity, through the activation of the nuclear factor (NF)‐κB pathway (Guglielmotto et al ., 2012). Therefore, Aβ oligomers and monomers have completely different pathologic and physiologic effects (Guglielmotto et al ., 2014). …”

Section: Discussionmentioning

confidence: 99%

“…Aβ1‐42 polymerization is believed to occur in sequential phases: First Aβ monomers aggregate into soluble oligomers that then form insoluble oligomers, generating protofibrils and fibrils (Hubin et al ., 2014). Soluble Aβ1‐42 oligomers constitute the more toxic form of the peptide (Bolmont et al ., 2007; Nimmrich & Ebert, 2009; Guglielmotto et al ., 2014). Monomers have been proposed to be involved, preferentially, in physiologic processes (Puzzo et al ., 2011; Piccini et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

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Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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SummaryThe mechanistic relationship between amyloid β1‐42 (Aβ1‐42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1‐42 monomers and oligomers on Tau, using mice expressing wild‐type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1‐42, mice were sacrificed after 3 h or 4 days. The short‐lasting treatment with Aβ monomers, but not oligomers, showed a conformational PHF‐like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aβ monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aβ oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aβ1‐42 monomers foster synaptic activity. Our results suggest that Aβ monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti‐Aβ therapies should be targeted to Aβ1‐42 monomers too.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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“…Neurotoxic prion protein (PrP) oligomers caused neuronal apoptosis via regulation of Bcl-2, Bax, and caspase-3 [37]. Both Aβ1-42 monomers and oligomers could induce cell apoptosis through different mechanisms, of which Aβ1-42 oligomers favored the formation of the Bcl2-BECN1 complex to induce apoptosis [38]. Of note, cell stimulation with H 2 O 2 resulted in peroxiredoxin-I (PRX-I) oxidation to form homo-oligomers which activated mammalian Sterile 20-like kinase 1 and induced apoptosis.…”

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confidence: 99%

Human eukaryotic elongation factor 1A forms oligomers through specific cysteine residues

Liu

Wang

et al. 2015

ABBS

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Eukaryotic elongation factor 1A (eEF1A) is a multifunctional protein involved in bundling actin, severing microtubule, activating the phosphoinositol-4 kinase, and recruiting aminoacyl-tRNAs to ribosomes during protein biosynthesis. Although evidence has shown the presence of the isoform eEF1A1 oligomers, the substantial mechanism of the self-association remains unclear. Herein, we found that human eEF1A1 could spontaneously form oligomers. Specifically, mutagenesis screen on cysteine residues demonstrated that Cys 234 was essential for eEF1A1 oligomerization. In addition,we also found that hydrogen peroxide treatment could induce the formation of eEF1A oligomers in cells. By cysteine replacement, eEF1A2 isoform displayed the ability to oligomerize in cells under the oxidative environment. In summary, in this study we characterized eEF1A1 oligomerization and demonstrated that specific cysteine residues are required for this oligomerization activity.

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“…However, overexpression of APP might cause mislocalization of APP, and as such, the toxic effects of Aβ derived from overexpressed APP on cellular homeostasis are difficult to evaluate. In addition, Aβ42 has also been observed in autophagosomes in neurons of AD patients (Nixon et al, 2000(Nixon et al, , 2005, which has also been implicated in Aβ42 metabolism (Lunemann et al, 2007;Guglielmotto et al, 2014;Nilsson et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Synthesized Aβ42 Caused Intracellular Oxidative Damage, Leading to Cell Death, via Lysosome Rupture

Oku

Murakami

Irie

et al. 2017

Cell Struct. Funct.

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ABSTRACT. Neuronal cellular accumulation of amyloid beta peptide (Aβ) has been implicated in the pathogenesis of Alzheimer's disease (AD). Intracellular accumulation of Aβ42, a toxic form of Aβ, was observed as an early event in AD patients. However, its contribution and the cellular mechanism of cell death remained unclear. We herein revealed the mechanism by which Aβ42 incorporated into cells leads to cell death by using chemically synthesized Aβ42 variants. The Aβ42 variant Aβ42 (E22P) which has an increased tendency to oligomerize, accumulated in lysosomes at an earlier stage than wild-type Aβ42, leading to higher ROS production and lysosomal membrane oxidation, and resulting in cell death. On the other hand, Aβ42 (E22V), which is incapable of oligomerization, did not accumulate in cells or affect the cell viability. Moreover, intracellular localization of EGFP-Galectin-3, a β-galactoside binding lectin, showed that accumulation of oligomerized Aβ42 in lysosomes caused lysosomal membrane permeabilization (LMP). Overexpression of lysosome-localized LAMP1-fused peroxiredoxin 1 and treatment with U18866A, an inhibitor of cholesterol export from lysosomes that causes an increase in lysosomal membrane stability, attenuated Aβ42-mediated LMP and cell death. Our findings show that lysosomal ROS generation by toxic conformer of Aβ led to cell death via LMP, and suggest that these events are potential targets for AD prevention.

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Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis

Cited by 72 publications

References 55 publications

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Human eukaryotic elongation factor 1A forms oligomers through specific cysteine residues

Synthesized Aβ42 Caused Intracellular Oxidative Damage, Leading to Cell Death, via Lysosome Rupture

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