Tau reduction prevents Aß-induced axonal transport deficits by blocking activation of GSK3ß

Vossel, Keith A.; Xu, Jie; Fomenko, Vira; Miyamoto, T.; Suberbielle, Elsa; Knox, Joseph A.; Ho, Kaitlyn; Kim, D; Gui, Yu; Mucke, Lennart

doi:10.1084/jem.2125oia25

Cited by 11 publications

(14 citation statements)

References 1 publication

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“…AD-associated presenilin 1 mutations and hyperphosphorylated tau have also been shown to induce axonal transport defects through activation of GSK3b [25,96,98]. Correcting fast axonal transport defects by reducing GSK3b activity was found to be beneficial in a Drosophila model of AD [99,100]. Deregulation of Cdk5 is also linked to defects in the slow axonal transport of neurofilaments in AD [77].…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Regulation of Axonal Transport by Protein Kinases

Gibbs

Greensmith

Schiavo

2015

Trends in Biochemical Sciences

108

102

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The intracellular transport of organelles, proteins, lipids, and RNA along the axon is essential for neuronal function and survival. This process, called axonal transport, is mediated by two classes of ATP-dependent motors, kinesins, and cytoplasmic dynein, which carry their cargoes along microtubule tracks. Protein kinases regulate axonal transport through direct phosphorylation of motors, adapter proteins, and cargoes, and indirectly through modification of the microtubule network. The misregulation of axonal transport by protein kinases has been implicated in the pathogenesis of several nervous system disorders. Here, we review the role of protein kinases acting directly on axonal transport and discuss how their deregulation affects neuronal function, paving the way for the exploitation of these enzymes as novel drug targets.

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Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Regulation of Axonal Transport by Protein Kinases

Gibbs

Greensmith

Schiavo

2015

Trends in Biochemical Sciences

108

102

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“…Tau plays a role in neuronal excitability and is required for Aβ and other excitotoxins to execute their degenerative effect, such as aberrant network activity and cognitive decline . In primary neurons prepared from mice expressing mutant human APP tau allows Aβ oligomers to inhibit axonal transport through activation of GSK3β . Genetic ablation of Tau decreases spontaneous seizures in APP transgenic mice and even in a non‐AD epilepsy model .…”

Section: Introductionmentioning

confidence: 99%

The Tau/A152T mutation, a risk factor for frontotemporal‐spectrum disorders, leads to NR 2B receptor‐mediated excitotoxicity

et al. 2016

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We report on a novel transgenic mouse model expressing human full-length Tau with the Tau mutation A152T (hTau AT ), a risk factor for FTD-spectrum disorders including PSP and CBD. Brain neurons reveal pathological Tau conformation, hyperphosphorylation, mis-sorting, aggregation, neuronal degeneration, and progressive loss, most prominently in area CA3 of the hippocampus. The mossy fiber pathway shows enhanced basal synaptic transmission without changes in short-or long-term plasticity. In organotypic hippocampal slices, extracellular glutamate increases early above control levels, followed by a rise in neurotoxicity. These changes are normalized by inhibiting neurotransmitter release or by blocking voltage-gated sodium channels. CA3 neurons show elevated intracellular calcium during rest and after activity induction which is sensitive to NR2B antagonizing drugs, demonstrating a pivotal role of extrasynaptic NMDA receptors. Slices show pronounced epileptiform activity and axonal sprouting of mossy fibers. Excitotoxic neuronal death is ameliorated by ceftriaxone, which stimulates astrocytic glutamate uptake via the transporter EAAT2/GLT1. In summary, hTau AT causes excitotoxicity mediated by NR2B-containing NMDA receptors due to enhanced extracellular glutamate.

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“…Kinesins are involved in the transport of cellular cargoes, including axonal transport. However, deficits in axonal transport have already been found to contribute to pathogenesis in AD patients and animal models . In addition, it has been shown that the axonal transport of APP is dependent on kinesin‐1 and that APP might be a membrane cargo receptor for kinesin‐1 .…”

mentioning

confidence: 99%

Kinesin‐1 inhibits the aggregation of amyloid‐β peptide as detected by fluorescence cross‐correlation spectroscopy

Zheng

Tian

et al. 2016

FEBS Letters

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Although the exact etiology and pathogenesis of Alzheimer's disease (AD) are still unclear, amyloid-b (Ab) generated by the proteolytic processing of amyloid-b precursor protein (APP) aggregate to form toxic amyloid species. Kinesin-1 is the first identified ATP-dependent axonal transport motor protein that has been proven to affect Ab generation and deposition. In this paper, we applied dual-color fluorescence cross-correlation spectroscopy (DC-FCCS) to investigate the direct interaction of Ab with kinesin-1 at the singlemolecule fluorescence level in vitro. The results showed that two kinds of enhanced green fluorescent protein (EGFP)-tagged kinesin light-chain subunits of kinesin-1(KLCs), KLC-E and E-KLC inhibited the aggregation of Ab over a period of time, providing additional insight into the mechanism of axonal transport deficits in AD.

show abstract

Tau reduction prevents Aß-induced axonal transport deficits by blocking activation of GSK3ß

Cited by 11 publications

References 1 publication

Regulation of Axonal Transport by Protein Kinases

Regulation of Axonal Transport by Protein Kinases

The Tau/A152T mutation, a risk factor for frontotemporal‐spectrum disorders, leads to NR 2B receptor‐mediated excitotoxicity

Kinesin‐1 inhibits the aggregation of amyloid‐β peptide as detected by fluorescence cross‐correlation spectroscopy

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