Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β

Vossel, Keith A.; Xu, Jane; Fomenko, Vira; Miyamoto, Takashi; Suberbielle, Elsa; Knox, Joseph A.; Ho, Kaitlyn; Kim, Daniel H.; Gui, Yu; Mucke, Lennart

doi:10.1083/jcb.201407065

Cited by 140 publications

(109 citation statements)

References 95 publications

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“…Ab-Mediated Synaptic Dysfunction by Eg5 Inhibition functions (reviewed in Mucke and Selkoe, 2012), including membrane trafficking (Umeda et al, 2015;Vossel et al, 2015). Accordingly, a recent study found that tau can also inhibit Eg5 activity; thus, Ab may inhibit Eg5 not only directly but also indirectly via regulation of tau (Bougé and Parmentier, 2016).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Freund¹,

Gibson²,

Potter³

et al. 2016

Mol Pharmacol

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Alzheimer's disease (AD) is characterized by neurofibrillary tangles, amyloid plaques, and neurodegeneration. However, this pathology is preceded by increased soluble amyloid beta (Ab) 1242 oligomers that interfere with the glutamatergic synaptic plasticity required for learning and memory, including N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). In particular, soluble Ab(1-42) acutely inhibits LTP and chronically causes synapse loss. Many mechanisms have been proposed for Ab-induced synaptic dysfunction, but we recently found that Ab(1-42) inhibits the microtubule motor protein Eg5/kinesin-5. Here we compared the impacts of Ab(1-42) and monastrol, a small-molecule Eg5 inhibitor, on LTP in hippocampal slices and synapse loss in neuronal cultures. Acute (20-minute) treatment with monastrol, like Ab, completely inhibited LTP at doses .100 nM. In addition, 1 nM Ab(1-42) or 50 nM monastrol inhibited LTP~5 0%, and when applied together caused complete LTP inhibition. At concentrations that impaired LTP, neither Ab(1-42) nor monastrol inhibited NMDAR synaptic responses until 60 minutes, when only~25% inhibition was seen for monastrol, indicating that NMDAR inhibition was not responsible for LTP inhibition by either agent when applied for only 20 minutes. Finally, 48 hours of treatment with either 0.5-1.0 mM Ab(1-42) or 1-5 mM monastrol reduced the dendritic spine/synapse density in hippocampal cultures up to a maximum of~40%, and when applied together at maximal concentrations, no additional spine loss resulted. Thus, monastrol can mimic and in some cases occlude the impact of Ab on LTP and synapse loss, suggesting that Ab induces acute and chronic synaptic dysfunction in part through inhibiting Eg5.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Freund¹,

Gibson²,

Potter³

et al. 2016

Mol Pharmacol

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“…It was hypothesized that alterations in synaptic mitochondria develops earlier than in non-synaptic mitochondria [87]. It seems that tau is required for Aβ-induced impairment of axonal transport, which process is presumably initiated via the activation of NMDARs, glycogen synthase kinase 3β (GSK3β), and casein kinase 2 (CK2) [84,88,89]. Naturally, the above detailed three main aspects of mitochondrial dysfunction act synergistically: the activation of Drp1 and Fis1 by free radicals resulted in mitochondrial fragmentation, their altered synaptic transport, and consequentially reduced synaptic ATP levels and dysfunction [87].…”

Section: Mitochondrial Disturbances In Alzheimer's Diseasementioning

confidence: 99%

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Zádori

Veres

Szalárdy

et al. 2018

JAD

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The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathwayrelated alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.3

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“…While our work provides evidence that tau knockdown impairs learning and memory in wild‐type mice, a vast number of studies have shown that knockout of endogenous tau in AD mouse models protects against Aβ‐induced cognitive deficits (Ittner et al., 2010; Ke et al., 2012; Roberson et al., 2011; Vossel et al., 2015). For example, crossing APP mice with tau knockout mice improved spatial reference memory (Roberson et al., 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Overall, the Tet/U6 included seven Tet operator sequences. Notably, the ShRNA sequence for tau was obtained from a previous publication (Vossel et al., 2015). The experimental virus was generated to target the MAPT gene through the usage of a doxycycline‐inducible ShRNA.…”

Section: Methodsmentioning

confidence: 99%

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

et al. 2018

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SummaryMisfolded and hyperphosphorylated tau accumulates in several neurodegenerative disorders including Alzheimer's disease, frontotemporal dementia with Parkinsonism, corticobasal degeneration, progressive supranuclear palsy, Down syndrome, and Pick's disease. Tau is a microtubule‐binding protein, and its role in microtubule stabilization is well defined. In contrast, while growing evidence suggests that tau is also involved in synaptic physiology, a complete assessment of tau function in the adult brain has been hampered by robust developmental compensation of other microtubule‐binding proteins in tau knockout mice. To circumvent these developmental compensations and assess the role of tau in the adult brain, we generated an adeno‐associated virus (AAV) expressing a doxycycline‐inducible short‐hairpin (Sh) RNA targeted to tau, herein referred to as AAV‐ShRNATau. We performed bilateral stereotaxic injections in 7‐month‐old C57Bl6/SJL wild‐type mice with either the AAV‐ShRNATau or a control AAV. We found that acute knockdown of tau in the adult hippocampus significantly impaired motor coordination and spatial memory. Blocking the expression of the AAV‐ShRNATau, thereby allowing tau levels to return to control levels, restored motor coordination and spatial memory. Mechanistically, the reduced tau levels were associated with lower BDNF levels, reduced levels of synaptic proteins associated with learning, and decreased spine density. We provide compelling evidence that tau is necessary for motor and cognitive function in the adult brain, thereby firmly supporting that tau loss‐of‐function may contribute to the clinical manifestations of many tauopathies. These findings have profound clinical implications given that anti‐tau therapies are in clinical trials for Alzheimer's disease.

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Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β

Abstract: Tau ablation, knockdown, and reconstitution studies in primary mouse neurons show that tau enables amyloid β oligomers to inhibit axonal transport through activation of GSK3β and through functions of tau that do not depend on its microtubule binding activity.

Cited by 140 publications

References 95 publications

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

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