Tau Reduction Prevents Aβ-Induced Defects in Axonal Transport

Vossel, Keith A.; Zhang, Kai; Brodbeck, Jens; Daub, Aaron; Sharma, Punita; Finkbeiner, Steven; Cui, Bianxiao; Mucke, Lennart

doi:10.1126/science.1194653

Cited by 442 publications

(394 citation statements)

References 12 publications

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“…Neuronal axon–Schwann cell interaction(s) are essential for myelination, and myelin maintenance is a dynamic process tightly controlled by axon‐dependent transcription factors such as Krox20 and Oct6 (Murphy et al ., 1996; Decker et al ., 2006). In line with previous studies demonstrating an absence of axonal deficits in neurons of Tau−/− animals (Yuan et al ., 2008; Vossel et al ., 2010), there were no differences in mRNA levels of transcription factors that critically regulate myelination process and/or maintenance, for example, Krox20 and Oct6 (data not shown), suggesting no gross changes in myelin gene regulation of Tau−/− Schwann cells. Furthermore, supporting the involvement of Tau and other cytoskeletal elements in myelination process, previous evidence suggests that Tau strongly colocalizes with MBP in distal tips of oligodendrocytes (LoPresti et al ., 1995; Muller et al ., 1997), suggesting that transportation and/or local MBP translation may require microtubule cytoskeleton and might be controlled by Tau–Fyn interaction (Klein et al ., 2002).…”

Section: Discussionmentioning

confidence: 86%

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Lopes

Pinto

et al. 2016

Aging Cell

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SummaryDementia is the cardinal feature of Alzheimer's disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well‐established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor‐related tests, we herein provide evidence of an age‐dependent motor impairment in Tau−/− animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor‐related information. Specifically, we show that the sciatic nerve of old (17–22‐months) Tau−/− mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age‐matched wild‐type (Tau+/+) littermates and younger (4–6 months) Tau−/− and Tau+/+ mice. In addition, the sciatic nerves of Tau−/− mice exhibit a progressive hypomyelination (assessed by g‐ratio) specifically affecting large‐diameter, motor‐related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system.

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Section: Discussionmentioning

confidence: 86%

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Lopes

Pinto

et al. 2016

Aging Cell

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“…Tau absence confers neuroprotection in several models of neuronal damage, such as traumatic brain injury (Cheng et al , 2014), neuroinflammation (Maphis et al , 2015), amyloid β‐mediated excitotoxicity (Roberson et al , 2007, 2011; Ittner et al , 2010; Vossel et al , 2010), and epilepsy (Holth et al , 2013), among others. Given that acute stress negatively affects AHN (Gould et al , 1992) and considering the neuroprotection exerted by the lack of Tau in the aforementioned models, we addressed whether the Porsolt test would cause similar detrimental effects in Tau −/− and WT mice.…”

Section: Discussionmentioning

confidence: 99%

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

et al. 2016

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Tau is a microtubule‐associated neuronal protein found mainly in axons. However, its presence in dendrites and dendritic spines is particularly relevant due to its involvement in synaptic plasticity and neurodegeneration. Here, we show that Tau plays a novel in vivo role in the morphological and synaptic maturation of newborn hippocampal granule neurons under basal conditions. Furthermore, we reveal that Tau is involved in the selective cell death of immature granule neurons caused by acute stress. Also, Tau deficiency protects newborn neurons from the stress‐induced dendritic atrophy and loss of postsynaptic densities (PSDs). Strikingly, we also demonstrate that Tau regulates the increase in newborn neuron survival triggered by environmental enrichment (EE). Moreover, newborn granule neurons from Tau−/− mice did not show any stimulatory effect of EE on dendritic development or on PSD generation. Thus, our data demonstrate that Tau−/− mice show impairments in the maturation of newborn granule neurons under basal conditions and that they are insensitive to the modulation of adult hippocampal neurogenesis exerted by both stimulatory and detrimental stimuli.

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“…Tau knockout studies revealed that the Aβ-induced axonal transport deficits and impairment of hippocampal LTP were mediated by tau [58,59]. Reduction of endogenous tau was also shown to ameliorate cognitive behavioral deficits and the death rate of APP overexpressing mice [60][61][62].…”

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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Tau Reduction Prevents Aβ-Induced Defects in Axonal Transport

Cited by 442 publications

References 12 publications

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

Biometals and Their Therapeutic Implications in Alzheimer's Disease

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