Neuronal activity regulates extracellular tau in vivo

Yamada, Kaoru; Holth, Jerrah K.; Liao, Fan; Stewart, Floy R.; Mahan, Thomas E.; Jiang, Hong; Cirrito, John R.; Patel, Tirth K.; Hochgräfe, Katja; Mandelkow, Eva‐Maria; Holtzman, David M.

doi:10.1084/jem.20131685

Cited by 438 publications

(261 citation statements)

References 29 publications

Supporting

Mentioning

239

Contrasting

Order By: Relevance

“…In previous studies, we characterized the amount of tau within the interstitial fluid (ISF) as well as brain soluble and insoluble tau in P301S Tau Tg mice (26). ISF tau represents tau present in the extracellular space of the brain that is released from neurons (11). It is only a small fraction of the soluble brain tau assessed biochemically, which is predominantly composed of cytosolic tau.…”

Section: Resultsmentioning

confidence: 99%

“…It is also released by neurons in the brain physiologically and can be detected in soluble forms in brain ISF and CSF (10, 11). In brain ISF, tau has a long half-life, ~11 days in mice (31).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the fact that tau is predominantly a cytosolic protein, it is normally released into the extracellular space from neural cells and its release is regulated by excitatory neuronal activity (10, 11). A number of studies in animal models have shown that both active and passive immunization targeting tau can have beneficial effects on reducing tau pathology and improving function (12–19).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy

et al. 2017

Self Cite

View full text Add to dashboard Cite

Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…The exact biological role of T‐tau is not clear; it is from a biomarker perspective thought to be a surrogate marker of neurodegeneration33 which is elevated in AD and some other neurodegenerative diseases, although interestingly not in all tau‐opathies. However, it is becoming apparent that tau may not be a simple damage biomarker, but is secreted from cells under physiological conditions, a process which is regulated by neuronal activity 34, 3536 is elevated in neurodegeneration independent of amyloid deposition,27 and has been shown to be a prognostic marker in a large number of different neurodegenerative conditions 37, 38.…”

Section: Discussionmentioning

confidence: 99%

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Wellington¹,

Paterson

Suárez‐González

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveTo assess whether high levels of cerebrospinal fluid neurogranin are found in atypical as well as typical Alzheimer's disease.MethodsImmunoassays were used to measure cerebrospinal fluid neurogranin in 114 participants including healthy controls (n = 27), biomarker‐proven amnestic Alzheimer's disease (n = 68), and the atypical visual variant of Alzheimer's (n = 19) according to international criteria. CSF total‐tau, Aβ42, and neurofilament light concentrations were investigated using commercially available assays. All affected individuals had T1‐weighted volumetric MR images available for analysis of whole and regional brain volumes. Associations between neurogranin, brain volumes, total‐tau, Aβ42, and neurofilament light were assessed.ResultsMedian cerebrospinal fluid neurogranin concentrations were higher in typical and atypical Alzheimer's compared to controls (P < 0.001 and P = 0.005). Both neurogranin and total‐tau concentrations, but not neurofilament light and Aβ42, were higher in typical Alzheimer's compared to atypical patients (P = 0.004 and P = 0.03). There were significant differences in the left hippocampus and right and left superior parietal lobules in atypical patients, which were larger (P = 0.03) and smaller (P = 0.001 and P < 0.001), respectively, compared to typical patients. We found no evidence of associations between neurogranin and brain volumes but a strong association with total‐tau (P < 0.001) and a weaker association with neurofilament light (P = 0.005).InterpretationThese results show significant differences in neurogranin and total‐tau between typical and atypical patients, which may relate to factors other than disease topography. The differential relationships between neurogranin, total‐tau and neurofilament light in the Alzheimer's variants, provide evidence for mechanistically distinct and coupled markers of neurodegeneration.

show abstract

“…For example, NMDA receptormediated signalling influences the cleavage of tau by calpains and also tau phosphorylation by kinases, such as extracellularsignal-related kinase (ERK) [45]. Furthermore, stimulating NMDA receptor activity elevates neuronal tau release in vivo [46]. The trans-synaptic spread of tau pathology in AD is thought to underlie the progression of disease through anatomically connected brain regions [47] and thus it is possible that inflammatory mediators such as IL-18 may influence tau transmission via an effect on NMDA receptor function.…”

Section: Targeting Specific Inflammatory Signalling Pathwaysmentioning

confidence: 99%

Astrocytes and neuroinflammation in Alzheimer's disease

Phillips

Croft

Kurbatskaya

et al. 2014

Biochemical Society Transactions

View full text Add to dashboard Cite

Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.

show abstract

Neuronal activity regulates extracellular tau in vivo

Abstract: Neuronal activity promotes the release of extracellular tau in vivo.

Cited by 438 publications

References 29 publications

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Astrocytes and neuroinflammation in Alzheimer's disease

Contact Info

Product

Resources

About