Alzheimer disease

Nussbaum, Justin; Seward, Matthew E.; Bloom, George S.

doi:10.4161/pri.22118

Cited by 108 publications

(38 citation statements)

References 82 publications

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“…A growing body of evidence from human AD brain [2], AD model mouse brain [3–5], and cultured cells [6–8, 34, 38–40] has indicated that intracellular tau aggregation can be triggered by a prion-like mechanism [10, 12, 41] following uptake of aggregated extracellular tau. Mechanistic insight into this process has come primarily from cultured cell studies, many of which have made use of extracellular filaments made from tau fragments corresponding to the MT-binding repeat domains (tau-RD) and non-neuronal cells stably transfected to express tau-RD.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

Swanson

Breckenridge

McMahon

et al. 2017

JAD

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Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer’s disease and non-Alzheimer’s tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport.

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Section: Discussionmentioning

confidence: 99%

Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

Swanson

Breckenridge

McMahon

et al. 2017

JAD

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“…Two of the most remarkable features of AD are the stereotypic patterns by which plaques and tangles spread through the brain, 30 and the ability of toxic, misfolded AβOs and tau to serve as templates that convert their innocuous counterparts into equivalent pathological forms by a prionlike process in vitro 13,[31][32][33] and in vivo. [34][35][36][37][38] Several in-depth reviews on these topics have been published recently, [39][40][41][42] so no duplication of those efforts will be made here. However, they are mentioned in this review because they raise the question of how toxic posttranslational modifications of tau, like those that cause cell cycle reentry, 14 might relate to the misfolding and acquisition of prionlike properties by tau.…”

Section: Prionlike Properties Of Toxic Aβ and Taumentioning

confidence: 99%

Amyloid-β and Tau

2014

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“…Unlike Aβ, tau exhibits an anatomically stereotypical propagation pattern in the brain. A growing body of evidence indicates that tau spreads through the brain from neurons to nearby neurons in a prion-like fashion [5,11–14]. Studies in mouse models have shown that the characteristic patterns of tau spatial spread associated with AD progression are determined by neural connectivity rather than physical proximity between different brain regions [1].…”

Section: Introductionmentioning

confidence: 99%

A Longitudinal Model for Tau Aggregation in Alzheimer’s Disease Based on Structural Connectivity

Yang

Chowdhury

Jacobs

et al. 2019

Lecture Notes in Computer Science

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Tau tangles are a pathological hallmark of Alzheimer?s disease (AD) with strong correlations existing between tau aggregation and cognitive decline. Studies in mouse models have shown that the characteristic patterns of tau spatial spread associated with AD progression are determined by neural connectivity rather than physical proximity between different brain regions. We present here a network diffusion model for tau aggregation based on longitudinal tau measures from positron emission tomography (PET) and structural connectivity graphs from diffusion tensor imaging (DTI). White matter fiber bundles reconstructed via tractography from the DTI data were used to compute normalized graph Laplacians which served as graph diffusion kernels for tau spread. By linearizing this model and using sparse source localization, we were able to identify distinct patterns of propagative and generative buildup of tau at a population level. A gradient descent approach was used to solve the sparsity-constrained optimization problem. Model fitting was performed on subjects from the Harvard Aging Brain Study cohort. The fitted model parameters include a scalar factor controlling the network-based tau spread and a network-independent seed vector representing seeding in different regions-of-interest. This parametric model was validated on an independent group of subjects from the same cohort. We were able to predict with reasonably high accuracy the tau buildup at a future time-point. The network diffusion model, therefore, successfully identifies two distinct mechanisms for tau buildup in the aging brain and offers a macroscopic perspective on tau spread.

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Alzheimer disease

Cited by 108 publications

References 82 publications

Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

Amyloid-β and Tau

A Longitudinal Model for Tau Aggregation in Alzheimer’s Disease Based on Structural Connectivity

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