HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

Tsushima, Hanako; Emanuele, Marco; Polenghi, Alice; Esposito, Alessandro; Vassalli, Massimo; Barberis, Andrea; Difato, Francesco; Chieregatti, Evelina

doi:10.1038/ncomms8781

Cited by 56 publications

(78 citation statements)

References 70 publications

(84 reference statements)

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“…As consequence, a correct cell morphology of neurons and astrocytes is restored. We thus provide a new mechanism of microtubule destabilization driven upstream by human AβOs, through the post-translational modulation of tau and tubulin, extending previous findings in AD neuronal models [39,40].…”

Section: Discussionsupporting

confidence: 76%

Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers

et al. 2019

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Alterations of adult neurogenesis have been reported in several Alzheimer's disease (AD) animal models and human brains, while defects in this process at presymptomatic/early stages of AD have not been explored yet. To address this, we investigated potential neurogenesis defects in Tg2576 transgenic mice at 1.5 months of age, a prodromal asymptomatic age in terms of Aβ accumulation and neurodegeneration. We observe that Tg2576 resident and SVZ-derived adult neural stem cells (aNSCs) proliferate significantly less. Further, they fail to terminally differentiate into mature neurons due to pathological, tau-mediated, and microtubule hyperstabilization. Olfactory bulb neurogenesis is also strongly reduced, confirming the neurogenic defect in vivo. We find that this phenotype depends on the formation and accumulation of intracellular A-beta oligomers (AβOs) in aNSCs. Indeed, impaired neurogenesis of Tg2576 progenitors is remarkably rescued both in vitro and in vivo by the expression of a conformation-specific anti-AβOs intrabody (scFvA13-KDEL), which selectively interferes with the intracellular generation of AβOs in the endoplasmic reticulum (ER). Altogether, our results demonstrate that SVZ neurogenesis is impaired already at a presymptomatic stage of AD and is caused by endogenously generated intracellular AβOs in the ER of aNSCs. From a translational point of view, impaired SVZ neurogenesis may represent a novel biomarker for AD early diagnosis, in association to other biomarkers. Further, this study validates intracellular Aβ oligomers as a promising therapeutic target and prospects anti-AβOs scFvA13-KDEL intrabody as an effective tool for AD treatment.

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Section: Discussionsupporting

confidence: 76%

Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers

et al. 2019

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“…A previous gene linkage study found a significant association between sporadic AD and the single‐nucleotide polymorphism of ANK3 . Mislocalization of ANK3 and its role in the disruption of axon polarity have been recently reported . Our findings of the marked decrease in ANK3 O‐GlcNAcylation in AD brains may open a new avenue for further investigation of its role in the molecular pathogenesis of AD, such as the influence of O‐GlcNAc of ANK3 in membrane integrity and axon polarity.…”

Section: Discussionsupporting

confidence: 66%

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Wang

Yang

Petyuk

et al. 2017

The Journal of Pathology

107

125

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Protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer’s disease, however detailed molecular characterization of this important protein posttranslational modification at proteome level has been highly challenging, due to its low stoichiometry and labile nature. Herein we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in post-mortem human brain tissues with and without Alzheimer’s disease using isobaric tandem mass tags labeling, chemoenzymatic photocleavage enrichment and liquid chromatography coupled to mass spectrometry. A total of 1,850 O-GlcNAc peptides covering 1,094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. One hundred and thirty one O-GlcNAc peptides covering 81 proteins were altered in Alzheimer’s brain as compared to controls (q <0.05). Moreover, alteration of O-GlcNAc peptide abundance could be attributed more to O-GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic Alzheimer’s disease.

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“…In a recent study on the brains of deceased patients with Alzheimer's disease, it was determined via quantitative Western blotting that the levels of total α‐tubulin were diminished relative to nondiseased brain, and so too were the levels of acetylated tubulin. However, the ratio of acetylated to total tubulin was increased, which would be consistent with a preferential loss of labile microtubule domains [Tsushima et al, ; Zhang et al, ]. If this is the case, just as with nerve injury discussed above, the more effective strategy may be one that increases labile microtubule mass.…”

Section: Microtubule Stability In Nervous System Diseasementioning

confidence: 73%

Stability properties of neuronal microtubules

et al. 2016

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Neurons are terminally differentiated cells that use their microtubule arrays not for cell division but rather as architectural elements required for the elaboration of elongated axons and dendrites. In addition to acting as compression-bearing struts that provide for the shape of the neuron, microtubules also act as directional railways for organelle transport. The stability properties of neuronal microtubules are commonly discussed in the biomedical literature as crucial to the development and maintenance of the nervous system, and have recently gained attention as central to the etiology of neurodegenerative diseases. Drugs that affect microtubule stability are currently under investigation as potential therapies for disease and injury of the nervous system. There is often a lack of consistency, however, in how the issue of microtubule stability is discussed in the literature, and this can affect the design and interpretation of experiments as well as potential therapeutic regimens. Neuronal microtubules are considered to be more stable than microtubules in dividing cells. On average, this is true, but in addition to an abundant stable microtubule fraction in neurons, there is also an abundant labile microtubule fraction. Both are functionally important. Individual microtubules consist of domains that differ in their stability properties, and these domains can also differ markedly in their composition as well as how they interact with various microtubule-related proteins in the neuron. Myriad proteins and pathways have been discussed as potential contributors to microtubule stability in neurons.

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HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

Cited by 56 publications

References 70 publications

Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers

Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Stability properties of neuronal microtubules

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