Advances in the Pathogenesis of Alzheimer’s Disease: Focusing on Tau-Mediated Neurodegeneration

Duan, Yale; Shen, Dong; Gu, Feng; Hu, Yinghe; Zheng, Zhao

doi:10.1186/2047-9158-1-24

Cited by 63 publications

(44 citation statements)

References 69 publications

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“…We wondered whether the transient changes in Purkinje cell torpedoes we observed were due to the presence of the tau-GFP protein in our transgenic mice, since tau is important for axonal integrity, and overexpressing tau can be pathological in Alzheimer Disease (Duan et al, 2012; Krstic and Knuesel, 2013). To determine whether our results were influenced by overexpression of tau, we examined Purkinje cell axons from C57BL6/J mice and counted the number of developmental torpedoes at three different ages: P7, P11, and P30 ( Figure 1E ; P7: 0.84 ± 0.26 torpedoes/section; P11: 5.6 ± 1.2 torpedoes/section; P30: 0.29 ± 0.08 torpedoes/section).…”

Section: Resultsmentioning

confidence: 99%

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Ljungberg

Lang-Ouellette

Yang

et al. 2016

Front. Cell. Neurosci.

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Information is carried out of the cerebellar cortical microcircuit via action potentials propagated along Purkinje cell axons. In several human neurodegenerative diseases, focal axonal swellings on Purkinje cells – known as torpedoes – have been associated with Purkinje cell loss. Interestingly, torpedoes are also reported to appear transiently during development in rat cerebellum. The function of Purkinje cell axonal torpedoes in health as well as in disease is poorly understood. We investigated the properties of developmental torpedoes in the postnatal mouse cerebellum of wild-type and transgenic mice. We found that Purkinje cell axonal torpedoes transiently appeared on axons of Purkinje neurons, with the largest number of torpedoes observed at postnatal day 11 (P11). This was after peak developmental apoptosis had occurred, when Purkinje cell counts in a lobule were static, suggesting that most developmental torpedoes appear on axons of neurons that persist into adulthood. We found that developmental torpedoes were not associated with a presynaptic GABAergic marker, indicating that they are not synapses. They were seldom found at axonal collateral branch points, and lacked microglia enrichment, suggesting that they are unlikely to be involved in axonal refinement. Interestingly, we found several differences between developmental torpedoes and disease-related torpedoes: developmental torpedoes occurred largely on myelinated axons, and were not associated with changes in basket cell innervation on their parent soma. Disease-related torpedoes are typically reported to contain neurofilament; while the majority of developmental torpedoes did as well, a fraction of smaller developmental torpedoes did not. These differences indicate that developmental torpedoes may not be functionally identical to disease-related torpedoes. To study this further, we used a mouse model of spinocerebellar ataxia type 6 (SCA6), and found elevated disease-related torpedo number at 2 years. However, we found normal levels of developmental torpedoes in these mice. Our findings suggest that the transient emergence of Purkinje cell axonal torpedoes during the second postnatal week in mice represents a normal morphological feature in the developing cerebellar microcircuit.

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Section: Resultsmentioning

confidence: 99%

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Ljungberg

Lang-Ouellette

Yang

et al. 2016

Front. Cell. Neurosci.

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“…reduction in microtubule mass) from axons and dendrites is often associated with neurodegenerative diseases (78, 79). This is best documented in diseases called tauopathies, in which tau dissociates from microtubules as a result of abnormal phosphorylation (80, 81). Pure tauopathies result from mutations that render tau prone to such effects.…”

Section: Microtubule Defects In Nervous System Diseasementioning

confidence: 99%

Microtubules in health and degenerative disease of the nervous system

Matamoros

Baas

2016

Brain Research Bulletin

113

112

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Microtubules are essential for the development and maintenance of axons and dendrites throughout the life of the neuron, and are vulnerable to degradation and disorganization in a variety of neurodegenerative diseases. Microtubules, polymers of tubulin heterodimers, are intrinsically polar structures with a plus end favored for assembly and disassembly and a minus end less favored for these dynamics. In the axon, microtubules are nearly uniformly oriented with plus ends out, whereas in dendrites, microtubules have mixed orientations. Microtubules in developing neurons typically have a stable domain toward the minus end and a labile domain toward the plus end. This domain structure becomes more complex during neuronal maturation when especially stable patches of polyaminated tubulin become more prominent within the microtubule. Microtubules are the substrates for molecular motor proteins that transport cargoes toward the plus or minus end of the microtubule, with motor-driven forces also responsible for organizing microtubules into their distinctive polarity patterns in axons and dendrites. A vast array of microtubule-regulatory proteins impart direct and indirect changes upon the microtubule arrays of the neuron, and these include microtubule-severing proteins as well as proteins responsible for the stability properties of the microtubules. During neurodegenerative diseases, microtubule mass is commonly diminished, and the potential exists for corruption of the microtubule polarity patterns and microtubule-mediated transport. These ill effects may be a primary causative factor in the disease or may be secondary effects, but regardless, therapeutics capable of correcting these microtubule abnormalities have great potential to improve the status of the degenerating nervous system.

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“…Many studies imply that numerous kinases are involved in hyperphosphorylation of tau, including cyclin-dependent kinase 5 (CDK5), GSK3, ERK2 and MT-affinity-regulating kinase (MARK). They have been proved to be the upstream modulators of the phosphorylation in AD (Duan et al, 2012). In these kinases, CDK5 and GSK3 have been shown to be associated with all stages of neurofibrillary pathology in AD (Iqbal et al, 2009).…”

Section: Microtubule-stabilizing Proteins Taumentioning

confidence: 98%

Role of cytoskeleton in axonal regeneration after neurodegenerative diseases and CNS injury

Li¹,

Zhu²,

Chen³

et al. 2014

Reviews in the Neurosciences

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Advances in the Pathogenesis of Alzheimer’s Disease: Focusing on Tau-Mediated Neurodegeneration

Cited by 63 publications

References 69 publications

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Microtubules in health and degenerative disease of the nervous system

Role of cytoskeleton in axonal regeneration after neurodegenerative diseases and CNS injury

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