Axodendritic sorting and pathological missorting of Tau are isoform-specific and determined by axon initial segment architecture

Zempel, Hans; Dennissen, Frank J.A.; Kumar, Yatender; Luedtke, Julia; Biernat, Jacek; Mandelkow, Eva‐Maria; Mandelkow, Eckhard

doi:10.1074/jbc.m117.784702

Cited by 110 publications

(171 citation statements)

References 67 publications

Supporting

Mentioning

166

Contrasting

Order By: Relevance

“…This suggests either a selective vulnerability of the distal axonal segment, or protection against tau misfolding in proximal axonal regions. The region of the axon initial segment has been shown to act as a barrier for select isoforms of tau proteins, potentially due to increased microtubule dynamics in this area 46,47 , which may play a role in the lack of retention of misfolded tau within this region. However, it is clear that misfolded tau is able to cross this barrier and cause distal axon pathology.…”

Section: Discussionmentioning

confidence: 99%

Efficient propagation of misfolded tau between individual neurons occurs in absence of degeneration

Hallinan

Vargas‐Caballero

West

et al. 2018

Preprint

View full text Add to dashboard Cite

In Alzheimer's disease, misfolded tau protein propagates through the brain in a prion-like manner along connected circuits. Tauopathy correlates with significant neuronal death, but the links between tau aggregation, propagation, neuronal dysfunction and death remain poorly understood, and the direct functional consequences for the neuron containing the tau aggregates are unclear. Here, by monitoring individual neurons within a minimal circuit, we demonstrate that misfolded tau efficiently spreads from presynaptic to postsynaptic neurons.Within postsynaptic cells, tau aggregates initially in distal axons, while proximal axons remain free of tau pathology. In the presence of tau aggregates neurons display axonal transport deficits, but remain viable and electrically competent. This shows that misfolded tau species are not immediately toxic to neurons, and suggests that propagation of misfolded tau is an early event in disease, occurring prior to neuronal dysfunction and cell death.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/372029 doi: bioRxiv preprint first posted online Jul. 18, 2018; Neurofibrillary tangles (NFTs), a pathological hallmark of Alzheimer's disease (AD), consist of insoluble aggregates of hyperphosphorylated tau protein. In AD, NFTs accumulate first in the entorhinal cortex, and with disease progression they appear in neighbouring regions such as the hippocampus, followed by the neocortex in later stages 1 . The neuroanatomical localisation of NFTs in AD brains suggests that tau pathology propagates through the brain along anterograde connected brain circuits 2-4 . Indeed, it is well established that pathogenic tau spreads between cells in vitro 5,6 and in vivo 4,7,8 in a prion-like manner, inducing the misfolding of native tau 5,[9][10][11] . Tau seeds, the tau species that template a misfolded conformation to native tau, are thought to be monomers or lower molecular weight oligomers rather than the high molecular weight tangles observed at late stages of disease, but their exact nature is still under debate [12][13][14][15][16] . Moreover, experiments using AD brain extracts to seed the misfolding of tau reported the existence of distinct pathological tau strains 6.Pathogenic tau causes cell death both in vivo 4 and in vitro 17,18 . Therefore, it has been suggested that one mechanism for the propagation of tau pathology is release following the disintegration and death of the tangle-bearing neurons 19 . In contrast, recent studies haveshown that intact neurons exist in areas of pathology propagation in mouse models 20, and have detected tau species capable of seeding misfolding in brain areas free of tangle pathology in human brains 21. This suggests potential release of pathogenic tau from living neurons. However, loss of neurons is progressive within areas affected by degeneration, ...

show abstract

Section: Discussionmentioning

confidence: 99%

Efficient propagation of misfolded tau between individual neurons occurs in absence of degeneration

Hallinan

Vargas‐Caballero

West

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Both intrinsic features of tau and extrinsic mechanisms may contribute to its dendritic and post-synaptic recruitment. Intrinsic properties of tau include isoform composition, since 2N tau showed a higher propensity for sorting into the somato-dendritic compartment, as compared to other tau variants (Zempel et al, 2017). Furthermore, a truncated tau variant lacking the MTRs after amino acid 255 did not distribute to dendritic compartments in cultured neurons and in transgenic mouse brains (Ittner et al, 2010).…”

Section: Regulatory Pathways Of Dendritic/post-synaptic Tau Localizationmentioning

confidence: 99%

“…The AIS was shown to limit the amount of tau relocalizing from axon to soma (Li et al, 2011). This retrograde diffusional restriction of tau may be governed by several protein-protein interactions of tau with AIS complexes (such as ankyrinG/EB1, GSK3b) (Zempel et al, 2017). Furthermore, post-translational modifications may affect axonal enrichment of tau as acetylation regulates tau sorting at the AIS in cultured neurons (Tsushima et al, 2015).…”

Section: Polarized Neuronal Distribution Of Taumentioning

confidence: 99%

Dendritic Tau in Alzheimer’s Disease

Ittner

2018

Neuron

201

199

View full text Add to dashboard Cite

The microtubule-associated protein tau and amyloid-β (Aβ) are key players in Alzheimer's disease (AD). Aβ and tau are linked in a molecular pathway at the post-synapse with tau-dependent synaptic dysfunction being a major pathomechanism in AD. Recent work on site-specific modification of dendritic and more specifically post-synaptic tau has revealed new endogenous functions of tau that limits synaptic Aβ toxicity. Thus, molecular studies opened a new perspective on tau, placing it at the center of neurotoxic and neuroprotective signaling at the post-synapse. Here, we review recent advances on tau in the dendritic compartments, with implications for understanding and treatment of AD and related neurological conditions.

show abstract

“…Hence, these findings show that activated cofilin can displace tau from microtubules, resulting not only in inhibition of tau-mediated microtubule dynamics but also tau hyperphosphorylation and tauopathy. Intriguingly, Zempel and colleagues showed that the axonal initial segment (AIS) of neurons contains a tau diffusion barrier composed of actin filaments that normally keeps tau in axons by preventing its retrograde traffic back to the soma [133]. A␤ oligomer-induced activation of cofilin at the AIS was found to dissolve the tau diffusion barrier, which allows missorting of tau to somatodendritic compartments [133].…”

Section: Cofilin In Tauopathymentioning

confidence: 99%

Cofilin, a Master Node Regulating Cytoskeletal Pathogenesis in Alzheimer’s Disease

Kang

Woo

2019

JAD

View full text Add to dashboard Cite

The defining pathological hallmarks of Alzheimer's disease (AD) are proteinopathies marked by the amyloid-␤ (A␤) peptide and hyperphosphorylated tau. In addition, Hirano bodies and cofilin-actin rods are extensively found in AD brains, both of which are associated with the actin cytoskeleton. The actin-binding protein cofilin known for its actin filament severing, depolymerizing, nucleating, and bundling activities has emerged as a significant player in AD pathogenesis. In this review, we discuss the regulation of cofilin by multiple signaling events impinging on LIM kinase-1 (LIMK1) and/or Slingshot homolog-1 (SSH1) downstream of A␤. Such pathophysiological signaling pathways impact actin dynamics to regulate synaptic integrity, mitochondrial translocation of cofilin to promote neurotoxicity, and formation of cofilin-actin pathology. Other intracellular signaling proteins, such as ␤-arrestin, RanBP9, Chronophin, PLD1, and 14-3-3 also impinge on the regulation of cofilin downstream of A␤. Finally, we discuss the role of activated cofilin as a bridge between actin and microtubule dynamics by displacing tau from microtubules, thereby destabilizing tau-induced microtubule assembly, missorting tau, and promoting tauopathy.

show abstract

Axodendritic sorting and pathological missorting of Tau are isoform-specific and determined by axon initial segment architecture

Cited by 110 publications

References 67 publications

Efficient propagation of misfolded tau between individual neurons occurs in absence of degeneration

Efficient propagation of misfolded tau between individual neurons occurs in absence of degeneration

Dendritic Tau in Alzheimer’s Disease

Cofilin, a Master Node Regulating Cytoskeletal Pathogenesis in Alzheimer’s Disease

Contact Info

Product

Resources

About