Global Axonal Transport Rates are Unaltered in Htau Mice in vivo

Yuan, Ao; Kumar, Asok; Sasaki, Takahiro; Duff, Karen; Nixon, Ralph A.

doi:10.3233/jad-130671

Cited by 13 publications

(10 citation statements)

References 35 publications

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“…Impairment of AT may result from the space-occupying nature of tau aggregates. (7) Some researchers reported lately that hTau mice expressing 3-fold higher levels of human tau in the absence of mouse tau also displayed normal fast and slow transport kinetics despite the presence of abnormally hyperphosphorylated tau in some neurons, consistent with their previous report that global AT rates in vivo are unaffected by deletion of endogenous tau or moderate overexpression of human tau in mice [62]. The results suggested that pathologically high levels of tau alone in hTau mice were insufficient to impair general AT function in vivo.…”

Section: Pathogenic Tau and Atsupporting

confidence: 72%

Axonal Transport Defects in Alzheimer’s Disease

Wang

Tan

2014

Mol Neurobiol

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A large body of evidences indicates that axonal transport (AT) defects play an important role in the pathogenesis of Alzheimer' disease (AD). AT, a critical cellular process for the maintenance and function of a neuron, requires components of the cytoskeletons as "tracks", motor proteins and ATP as "driving force", adaptor proteins to ensure the specific connection of the transported cargoes and motor proteins as well as active regulation. In AD pathology, AD-linked pathologic factors respectively perturb the four basic components of AT through different signaling pathways to cause AT defects. Mitochondrial transport, which is different from other transport cargoes, is also impaired via special pathways in AD. In this paper, we review the inhibitory effects of those factors on AT and their possible pathways, indicating these factors act in overlapping, synergistic, and circulating ways. Given the contributions of AT defects to AD, recent therapeutic studies focus on microtubule-stabilizing (MT-stabilizing) agents and alteration in phosphotransferase activities, and we propose more therapeutic strategies targeting AT defects.

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Section: Pathogenic Tau and Atsupporting

confidence: 72%

Axonal Transport Defects in Alzheimer’s Disease

Wang

Tan

2014

Mol Neurobiol

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“…Despite a plethora of recent reports, the role of tau in transport disruption is still a matter of debate. In vivo studies demonstrate that axonal transport is unaffected by tau overexpression or suppression, or by moderate amounts of hyperphosphorylated tau [ 67 , 68 ]. In primary culture, we have demonstrated that eAβO-induced BDNF-transport disruption is independent of tau [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Intracellular amyloid β oligomers impair organelle transport and induce dendritic spine loss in primary neurons

Umeda

Ramser

Yamashita

et al. 2015

acta neuropathol commun

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IntroductionSynaptic dysfunction and intracellular transport defects are early events in Alzheimer’s disease (AD). Extracellular amyloid β (Aβ) oligomers cause spine alterations and impede the transport of proteins and organelles such as brain-derived neurotrophic factor (BDNF) and mitochondria that are required for synaptic function. Meanwhile, intraneuronal accumulation of Aβ precedes its extracellular deposition and is also associated with synaptic dysfunction in AD. However, the links between intracellular Aβ, spine alteration, and mechanisms that support synaptic maintenance such as organelle trafficking are poorly understood.ResultsWe compared the effects of wild-type and Osaka (E693Δ)-mutant amyloid precursor proteins: the former secretes Aβ into extracellular space and the latter accumulates Aβ oligomers within cells. First we investigated the effects of intracellular Aβ oligomers on dendritic spines in primary neurons and their tau-dependency using tau knockout neurons. We found that intracellular Aβ oligomers caused a reduction in mushroom, or mature spines, independently of tau. We also found that intracellular Aβ oligomers significantly impaired the intracellular transport of BDNF, mitochondria, and recycling endosomes: cargoes essential for synaptic maintenance. A reduction in BDNF transport by intracellular Aβ oligomers was also observed in tau knockout neurons.ConclusionsOur findings indicate that intracellular Aβ oligomers likely contribute to early synaptic pathology in AD and argue against the consensus that Aβ-induced spine loss and transport defects require tau.

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“…Some researchers have proposed that the tau-mediated synaptic deficits are presynaptic as tau is typically localized to the axon. Deficits in axonal transport caused by the treatment of cultured neurons with soluble Ab oligomers are dependent on the presence of tau (Vossel et al, 2010); however, even a threefold increase in cellular tau is not sufficient to cause decreases in axonal transport rate, implying that tau works in concert with other factors to cause presynaptic deficits (Yuan et al, 2013). A recent line of evidence suggests that tauopathies may originate postsynaptically.…”

Section: Tau Mislocalization To Dendritic Spinesmentioning

confidence: 99%

Tau acts as a mediator for Alzheimer's disease‐related synaptic deficits

Liao

Miller

Teravskis

2014

Eur J of Neuroscience

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The two histopathological hallmarks of Alzheimer's disease (AD) are amyloid plaques containing multiple forms of Aβ and neurofibrillary tangles containing phosphorylated tau proteins. As mild cognitive impairment frequently occurs long before the clinical diagnosis of Alzheimer's disease, the scientific community has been increasingly interested in the roles of Aβ and tau in earlier cellular changes that lead to functional deficits. Therefore, great progress has recently been made in understanding how Aβ or tau causes synaptic dysfunction. However, the interaction between the Aβ and tau-initiated intracellular cascades that lead to synaptic dysfunction remains elusive. The cornerstone of the two decade-old hypothetical amyloid cascade model is that amyloid pathologies precede tau pathologies. Although the premise of Aβ-tau pathway remains valid, the model keeps evolving as new signaling events are discovered that lead to functional deficits and neurodegeneration. Recent progress has been made in understanding Aβ-PrPC-Fyn-mediated neurotoxicity and synaptic deficits. Although still elusive, many novel upstream and downstream signaling molecules have been found to modulate tau mislocalization and tau hyperphosphorylation. Here we will discuss the mechanistic interactions between Aβ-PrPC-mediated neurotoxicity and tau-mediated synaptic deficits in an updated amyloid cascade model with calcium and tau as the central mediators.

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Global Axonal Transport Rates are Unaltered in Htau Mice in vivo

Cited by 13 publications

References 35 publications

Axonal Transport Defects in Alzheimer’s Disease

Axonal Transport Defects in Alzheimer’s Disease

Intracellular amyloid β oligomers impair organelle transport and induce dendritic spine loss in primary neurons

Tau acts as a mediator for Alzheimer's disease‐related synaptic deficits

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