Spread of tau down neural circuits precedes synapse and neuronal loss in the rTgTauEC mouse model of early <scp>A</scp>lzheimer's disease

Pickett, Eleanor; Henstridge, Christopher M.; Allison, Elizabeth; Pitstick, Rose; Pooler, Amy M.; Wegmann, Susanne; Carlson, George A.; Hyman, Bradley T.; Spires‐Jones, Tara L.

doi:10.1002/syn.21965

Cited by 55 publications

(50 citation statements)

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“…Instead, they initiate a selective axonal transport dysfunction that precedes synaptic loss, and in isolation does not result in axonal degeneration or cell death. Furthermore, we provide the first direct evidence for the suggestion that disintegration or death of neurons containing tau seeds does not need to occur in order to propagate tau pathology 20 , and show that tau propagation precedes synaptic or neuronal degeneration. This is in agreement with a recent study showing that spread of tau seeds precedes tangle pathology in the human brain 21 .…”

Section: Discussionmentioning

confidence: 68%

“…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 have shown 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.…”

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confidence: 95%

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

Hallinan

Vargas‐Caballero

West

et al. 2018

Preprint

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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, ...

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Section: Discussionmentioning

confidence: 68%

mentioning

confidence: 95%

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

Hallinan

Vargas‐Caballero

West

et al. 2018

Preprint

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“…Array Tomography-The array tomography protocol was applied using previously described methods (17,18). Briefly, a 1 cm 3 section was taken from the superior frontal cortex was fixed, dehydrated and polymerized in 100% LR-white resin.…”

Section: Methodsmentioning

confidence: 99%

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid

Lleó

Nuñez‐Llaves

Alcolea

et al. 2019

Molecular & Cellular Proteomics

153

151

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A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsyntenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages (n ‫؍‬ 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold (p < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, p ‫؍‬ 0.04) in an independent cohort (n ‫؍‬ 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8fold, p < 0.04), a finding that was replicated (0.7 to 0.8fold, p < 0.05) for 6 proteins in a third cohort (n ‫؍‬ 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold (p < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD.

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“…Postmortem analysis in AD patients has shown the presence and symmetrical distribution of misfolded tau over pre‐ and postsynapses . Recent findings demonstrate the ability of human P301L tau to spread trans‐synaptically before the degeneration of axonal terminals rather than through leakage . Furthermore, Yoshiyama et al.…”

Section: Synaptically Connected Spreading Of Aggregatesmentioning

confidence: 97%

Transcellular Spreading of Tau in Tauopathies

2018

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Tau, a microtubule-associated protein playing a key role in a group of neurodegenerative diseases such as Alzheimer's disease, spreads throughout the brain, inducing pathology. A model akin to the spreading of prions has been raised owing to similar characteristics of inducing an abnormal protein conformation as a method of self-amplification, spreading protein aggregates over anatomically linked pathways. The search to identify the "seeds" that induce conformational change has received much attention; however, less is known about the mechanisms by which tau is transmitted from cell to cell, so-called "transcellular spreading". In this review, we gather evidence regarding the spreading of tau throughout the brain and provide an overview of methods by which tau can be released from neurons as well as taken up. Furthermore, we bring together mechanisms of neurotoxicity behind tau spreading. Advancing our understanding about the spreading of tau can guide the search for therapeutic options for multiple neurodegenerative diseases aggregating tau.

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Spread of tau down neural circuits precedes synapse and neuronal loss in the rTgTauEC mouse model of early Alzheimer's disease

Cited by 55 publications

References 38 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

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid

Transcellular Spreading of Tau in Tauopathies

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