Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Sun, Xiao; Wu, Yu; Gu, Mingxue; Liu, Zhuo; Ma, Yuanlin; Li, Jun; Zhang, Yan

doi:10.1073/pnas.1411837111

Cited by 59 publications

(65 citation statements)

References 48 publications

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“…Finally, we showed that ankG and sodium channels are dispersed along the axon on exposure to Ab. Consistently, a recent report showed defective filtering at the axon initial segment in cultured neurons from an AD mouse model 66 . In conclusion, as summarized in the model shown in Fig.…”

Section: Discussionsupporting

confidence: 81%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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Maintenance of neuronal polarity and regulation of cytoskeletal dynamics are vital during development and to uphold synaptic activity in neuronal networks. Here we show that soluble b-amyloid (Ab) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Ab with the extracellular membrane promotes RhoA activation, leading to growth cone collapse and neurite retraction, which might be responsible for hampered neuronal pathfinding and migration in Alzheimer's disease (AD). The inhibition of HDAC6 by Ab increases the level of heterodimeric acetylated tubulin and acetylated tau, both of which have been found altered in AD. We also find that the loss of HDAC6 activity perturbs the integrity of axon initial segment (AIS), resulting in mislocalization of ankyrin G and increased MT instability in the AIS concomitant with loss of polarized localization of tau and impairment of action potential firing.

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Section: Discussionsupporting

confidence: 81%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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“…AnkG gene variants and mutations have been consistently associated with in several neuropsychiatric disorders, including bipolar disorders and schizophrenia (Iqbal et al, 2013;Leussis et al, 2012). Furthermore, affected axonal transport is a key factor in most neurodegenerative diseases, and the gatekeeper function of the AIS could be implicated (Sun et al, 2014). Our structural work will hopefully open the way to a better understanding of the AIS crucial functions, in physiological as well as pathological contexts.…”

Section: Role Of Ankg In Regulating Protein Transport Trough the Aismentioning

confidence: 85%

Nanoscale architecture of the axon initial segment reveals an organized and robust scaffold

Leterrier

Potier

Caillol

et al. 2015

Preprint

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The Axon Initial Segment [AIS], located within the first 30 µm of the axon, has two essential roles: generating the action potential, and maintaining axonal identity. AIS assembly depends on an ankyrin G / ßIV-spectrin scaffold, but its macromolecular arrangement is unknown, precluding the mechanistic understanding of its functions. We quantitatively determined the AIS nanoscale architecture using STochastic Optical Reconstruction Microscopy [STORM]. First, we directly demonstrated the existence of an AIS 190-nm periodic submembrane lattice composed of alternated actin rings and ßIV-spectrin dimers. Next, we used antibodies against different domains of ankyrin G to map its 3D nanoscale positioning: multicolor STORM demonstrated that the two large isoforms of ankyrin G are radially oriented across the AIS, with a 30-nm radial extent. The robustness of the AIS nano-architecture features against cytoskeletal or pharmacological perturbations suggest their structural role in the overall stability of the compartment. This organized and robust nanoscale architecture likely underpins the AIS functions in physiological and pathological contexts.axon initial segment | cytoskeleton | ankyrin G | super-resolution microscopy

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“…Axonal pathology in the APP/PS1 mouse model of Alzheimer’s is due in part to a decrease in AnkG and thus impairment of the AIS, which can be rescued by forced expression of AnkG. 69 Further, CDK5 activation is altered in a number of neurodegenerative diseases including Alzheimer’s 70 and ALS 71 ; dysregulated CDK5 may adversely impact polarized sorting in neurons as well as affecting transport along the axon, leading to further enhancement of cellular stress.…”

Section: Discussionmentioning

confidence: 99%

CDK5‐dependent activation of dynein in the axon initial segment regulates polarized cargo transport in neurons

Klinman

Tokito

Holzbaur

2017

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The unique polarization of neurons depends on selective sorting of axonal and somatodendritic cargos to their correct compartments. Axodendritic sorting and filtering occurs within the axon initial segment (AIS). However, the underlying molecular mechanisms responsible for this filter are not well understood. Here, we show that local activation of the neuronal-specific kinase CDK5 is required to maintain AIS integrity, as depletion or inhibition of CDK5 induces disordered microtubule polarity and loss of AIS cytoskeletal structure. Furthermore, CDK5-dependent phosphorylation of the dynein regulator Ndel1 is required for proper re-routing of mislocalized somatodendritic cargo out of the AIS; inhibition of this pathway induces profound mis-sorting defects. While inhibition of the CDK5-Ndel1-Lis1-dynein pathway alters both axonal microtubule polarity and axodendritic sorting, we found that these defects occur on distinct timescales; brief inhibition of dynein disrupts axonal cargo sorting before loss of microtubule polarity becomes evident. Together, these studies identify CDK5 as a master upstream regulator of trafficking in vertebrate neurons, required for both AIS microtubule organization and polarized dynein-dependent sorting of axodendritic cargos, and support an ongoing and essential role for dynein at the AIS.

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Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Cited by 59 publications

References 48 publications

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

Nanoscale architecture of the axon initial segment reveals an organized and robust scaffold

CDK5‐dependent activation of dynein in the axon initial segment regulates polarized cargo transport in neurons

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