Seed‐competent high‐molecular‐weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients

Takeda, Shuko; Commins, Caitlin; DeVos, Sarah L.; Nobuhara, Chloe K.; Wegmann, Susanne; Roe, Allyson D.; Costantino, Isabel; Fan, Zhanyun; Nicholls, Samantha B.; Sherman, Alexis E.; Lipsanopoulos, Ana T. Trisini; Scherzer, Clemens R.; Carlson, George A.; Pitstick, Rose; Peskind, Elaine R.; Raskind, Murray A.; Li, Ge; Montine, Thomas J.; Frosch, Matthew P.; Hyman, Bradley T.

doi:10.1002/ana.24716

Cited by 94 publications

(111 citation statements)

References 30 publications

(77 reference statements)

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…Recent studies showed that a lot of the tau detected in cerebrospinal fluid from AD patients has a molecular weight similar to dimeric and oligomeric of truncated tau, at least as determined by size exclusion (Takeda et al . ); similar low‐molecular weight tau derived from rTg4510 mouse brain lysates did not support the aggregation of TauRDP301S in a cell assay designed to sensitively detect tau aggregation (Takeda et al . ).…”

Section: Resultsmentioning

confidence: 99%

Formation, release, and internalization of stable tau oligomers in cells

Wegmann

Nicholls

Takeda

et al. 2016

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Tau is a neuronal microtubule binding protein that, in Alzheimer’s disease and other neurodegenerative diseases, can form oligomeric and large fibrillar aggregates, which deposit in neurofibrillary tangles. Tau’s physiological state of multimerization appears to vary across conditions, and a stable dimeric form of soluble tau has been suggested from experiments using recombinant tau in vitro. We tested if tau dimerization, or oligomerization, also occurs in cells, and if soluble tau oligomers are relevant for the release and internalization of tau. We developed a sensitive tau split-luciferase assay to show the rapid intracellular formation of stable tau dimers that are released and taken up by cells. Our data further suggest that tau dimerization can be accelerated slightly by aggregation catalysts. We conclude that tau oligomers are a stable physiological form of tau, and that tau oligomerization does not necessarily lead to tau aggregation.

show abstract

Section: Resultsmentioning

confidence: 99%

Formation, release, and internalization of stable tau oligomers in cells

Wegmann

Nicholls

Takeda

et al. 2016

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Many forms of tau have been observed to be secreted in vitro including phosphorylated tau (Pooler, Phillips, et al, ; Saman et al, ) and C‐terminally truncated tau (Kanmert et al, ). Recent data from AD cerebrospinal fluid and brain samples indicates that high molecular weight tau species may be released from human neurons and are competent to induce tau seeding in cultured cells (Takeda et al, ). Several mechanisms of tau release have been proposed (reviewed by (Wang & Mandelkow, )) including exocytosis of tau, vesicle mediated release such as in exosomes (Saman et al, ), or synaptic vesicle release (Polanco, Scicluna, Hill, & Gotz, ).…”

Section: Discussionmentioning

confidence: 99%

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

Pickett

Henstridge

Allison

et al. 2017

Synapse

Self Cite

View full text Add to dashboard Cite

Synaptic dysfunction and loss is the strongest pathological correlate of cognitive decline in Alzheimer's disease (AD) with increasing evidence implicating neuropathological tau protein in this process. Despite the knowledge that tau spreads through defined synaptic circuits, it is currently unknown whether synapse loss occurs before the accumulation of tau or as a consequence. To address this, we have used array tomography to examine an rTgTauEC mouse model expressing a P301L human tau transgene and a transgene labeling cytoplasm red (tdTomato) and presynaptic terminals green (Synaptophysin‐EGFP). All transgenes are restricted primarily to the entorhinal cortex using the neuropsin promotor to drive tTA expression. It has previously been shown that rTgTauEC mice exhibit neuronal loss in the entorhinal cortex and synapse density loss in the middle molecular layer (MML) of the dentate gyrus at 24 months of age. Here, we observed the density of tau‐expressing and total presynapses, and the spread of tau into the postsynapse in the MML of 3–6, 9, and 18 month old red–green‐rTgTauEC mice. We observe no loss of synapse density in the MML up to 18 months even in axons expressing tau. Despite the maintenance of synapse density, we see spread of human tau from presynaptic terminals to postsynaptic compartments in the MML at very early ages, indicating that the spread of tau through neural circuits is not due to the degeneration of axon terminals and is an early feature of the disease process.

show abstract

“…In the CSF of AD patients and transgenic mice expressing human-type tau, seed-competent tau is present that can stimulate tauopathy in cultured cells (Takeda et al, 2016), and some tau seeds in AD CSF appear to be associated with extracellular vesicles (Wang et al, 2017). The seeding capability of CSF tau in vivo , however, has not been reported; because CSF Aβ does not readily seed plaques or CAA in APP-transgenic mice (Fritschi et al, 2014b) (see above), a similar analysis of in vivo tau seeding by CSF from patients with AD (and other tauopathies) in the appropriate models could be informative.…”

Section: The Prion-like Properties Of Aggregated Taumentioning

confidence: 99%

Prion-like mechanisms in Alzheimer disease

Walker

2018

Handbook of Clinical Neurology

View full text Add to dashboard Cite

Senile plaques and neurofibrillary tangles are the principal histopathologic hallmarks of Alzheimer disease. The essential constituents of these lesions are structurally abnormal variants of normally generated proteins: Aβ protein in plaques and tau protein in tangles. At the molecular level, both proteins in a pathogenic state share key properties with classic prions, i.e., they consist of alternatively folded, β-sheet-rich forms of the proteins that autopropagate by the seeded corruption and self-assembly of like proteins. Other similarities with prions include the ability to manifest as polymorphic and polyfunctional strains, resistance to chemical and enzymatic destruction, and the ability to spread within the brain and from the periphery to the brain. In Alzheimer disease, current evidence indicates that the pathogenic cascade follows from the endogenous, sequential corruption of Aβ and then tau. Therapeutic options include reducing the production or multimerization of the proteins, uncoupling the Aβ-tauopathy connection, or promoting the inactivation or removal of anomalous assemblies from the brain. Although aberrant Aβ appears to be the prime mover of Alzheimer disease pathogenesis, once set in motion by Aβ, the prion-like propagation of tauopathy may proceed independently of Aβ; if so, Aβ might be solely targeted as an early preventive measure, but optimal treatment of Alzheimer disease at later stages of the cascade could require intervention in both pathways.

show abstract

Seed‐competent high‐molecular‐weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients

Cited by 94 publications

References 30 publications

Formation, release, and internalization of stable tau oligomers in cells

Formation, release, and internalization of stable tau oligomers in cells

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

Prion-like mechanisms in Alzheimer disease

Contact Info

Product

Resources

About