O2‐03‐08: Abeta oligomers cause local missorting of endogenous tau into dendrites, tau phosphorylation, destruction of microtubules and spines

Zempel, Hans; Thies, Edda; Mandelkow, Eckhard; Mandelkow, E.

doi:10.1016/j.jalz.2010.05.321

Cited by 46 publications

(73 citation statements)

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“…These findings are similar to the results of a study by Zempel et al [44] . In addition to early loss of synapses, the missorting of endogenous Tau from mainly axonal to somatodendritic compartments is among the earliest visible changes in AD.…”

Section: Discussionsupporting

confidence: 93%

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Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

et al. 2015

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Aim:The proteolytic cleavage of Tau is involved in Aβ-induced neuronal dysfunction and cell death. In this study, we investigated whether atorvastatin could prevent Tau cleavage and hence prevent Aβ 1-42 oligomer (AβO)-induced neurotoxicity in cultured cortical neurons. Methods: Cultured rat hippocampal neurons were incubated in the presence of AβOs (1.25 µmol/L) with or without atorvastatin pretreatment. ATP content and LDH in the culture medium were measured to assess the neuronal viability. Caspase-3/7 and calpain protease activities were detected. The levels of phospho-Akt, phospho-Erk1/2, phospho-GSK3β, p35 and Tau proteins were measured using Western blotting. Results: Treatment of the neurons with AβO significantly decreased the neuronal viability, induced rapid activation of calpain and caspase-3/7 proteases, accompanied by Tau degradation and relatively stable fragments generated in the neurons. AβO also suppressed Akt and Erk1/2 kinase activity, while increased GSK3β and Cdk5 activity in the neurons. Pretreatment with atorvastatin (0.5, 1, 2.5 µmol/L) dose-dependently inhibited AβO-induced activation of calpain and caspase-3/7 proteases, and effectively diminished the generation of Tau fragments, attenuated synaptic damage and increased neuronal survival. Atorvastatin pretreatment also prevented AβO-induced decreases in Akt and Erk1/2 kinase activity and the increases in GSK3β and Cdk5 kinase activity. Conclusion: Atorvastatin prevents AβO-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting calpain-and caspasemediated Tau cleavage.

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Section: Discussionsupporting

confidence: 93%

“…In dendritic regions from which Tau has been lost there is a depletion of spines, a local increase in Ca 2+ , and a breakdown of microtubules. Tau in these regions shows elevated phosphorylation at certain sites that are diagnostic of AD-Tau [44] . Atorvastatin pretreatment prevented AβO-induced Tau missorting.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

et al. 2015

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“…Aβ induces tau hyperphosphorylation, aggregation, and enhances tau toxicity. Treating cell cultures with multiple forms of Aβ, including soluble Aβ1-42 [40], Aβ oligomer [41], and Aβ fibril [42] induces tau hyperphosphorylation. Aβ-induced tau hyperphosphorylation consequently caused microtubule disassembly [41,43], reduction of total soluble tau and an increase in tau fragments [44], missorting of tau into dendritic areas [41], activation of the nuclear transcription factor of activated T cells' apoptotic pathways [45,46], and cell toxicity [41,44].…”

Section: Challenges In Targeting Amyloidmentioning

confidence: 99%

“…Treating cell cultures with multiple forms of Aβ, including soluble Aβ1-42 [40], Aβ oligomer [41], and Aβ fibril [42] induces tau hyperphosphorylation. Aβ-induced tau hyperphosphorylation consequently caused microtubule disassembly [41,43], reduction of total soluble tau and an increase in tau fragments [44], missorting of tau into dendritic areas [41], activation of the nuclear transcription factor of activated T cells' apoptotic pathways [45,46], and cell toxicity [41,44]. 2xTg (tau and APP mutant) or 3xTg (tau, APP and PS mutant) mice exhibit enhanced neurofibrillary tangle formation [47][48][49][50], which was attributed to activation of glycogen synthase kinase (GSK)-3β and Cdk5 [49,51], and inhibited proteasome activity [50].…”

Section: Challenges In Targeting Amyloidmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…It has been shown that Ab is unable to induce neurite degeneration in neurons derived from tau knockout mouse 8 , and that deletion or reduction of endogenous tau prevents the cognitive deficits observed in human amyloid precursor protein transgenic mice 9 . The transport deficit induced by Ab was also shown to be dependent on tau 10 and exposure of cultured neurons to Ab leads to missorting of axonal tau into somatodendritic compartments, where it disrupts cytoskeletal components 11,12 . Alterations in neuronal polarity can lead not only to functional defects in axon potential propagation but also in the development of young neurons, with dysregulation of adult neurogenesis, a process that is specifically impaired in neurodegenerative diseases.…”

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confidence: 99%

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

et al. 2015

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Maintenance of neuronal polarity and regulation of cytoskeletal dynamics are vital during development and to uphold synaptic activity in neuronal networks. Here we show that soluble b-amyloid (Ab) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Ab with the extracellular membrane promotes RhoA activation, leading to growth cone collapse and neurite retraction, which might be responsible for hampered neuronal pathfinding and migration in Alzheimer's disease (AD). The inhibition of HDAC6 by Ab increases the level of heterodimeric acetylated tubulin and acetylated tau, both of which have been found altered in AD. We also find that the loss of HDAC6 activity perturbs the integrity of axon initial segment (AIS), resulting in mislocalization of ankyrin G and increased MT instability in the AIS concomitant with loss of polarized localization of tau and impairment of action potential firing.

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O2‐03‐08: Abeta oligomers cause local missorting of endogenous tau into dendrites, tau phosphorylation, destruction of microtubules and spines

Cited by 46 publications

References 0 publications

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

Biometals and Their Therapeutic Implications in Alzheimer's Disease

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

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