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:10.1083/jcb.2045oia31

Cited by 54 publications

(74 citation statements)

References 12 publications

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“…; Yamada et al . ). Thus, glutamate‐mediated exocytosis of tau may indicate one mechanism for the trans‐synaptic spread of tau pathology associated with synaptic activity.…”

Section: Discussionmentioning

confidence: 97%

Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression

Hunsberger

Weitzner

Rudy

et al. 2015

Journal of Neurochemistry

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In the years preceding a diagnosis of Alzheimer’s disease (AD), hyperexcitability of the hippocampus is a commonly observed phenomenon in those at risk for AD. Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for ALS that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved memory performance that was associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus (DG), cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. Riluzole treatment also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter (vGLUT1), and the TauP301L-mediated decrease in hippocampal glutamate transporter 1 (GLT-1) and PSD-95 expression. Riluzole treatment also reduced tau pathology. These findings further elucidate the changes in glutamate regulation associated with tau pathology and open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD.

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“…; Yamada et al . ). Thus, glutamate‐mediated exocytosis of tau may indicate one mechanism for the trans‐synaptic spread of tau pathology associated with synaptic activity.…”

Section: Discussionmentioning

confidence: 97%

Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression

Hunsberger

Weitzner

Rudy

et al. 2015

Journal of Neurochemistry

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“…); pre‐synaptic release is consistent with recent results that extracellular tau levels are regulated by neuronal activity (Yamada et al . ). In particular, increased tau release by AD synapses documents a mechanism long observed in human pathology and shown in vivo for the regional spread of tau pathology (Braak and Del Tredici ; de Calignon et al .…”

Section: Discussionmentioning

confidence: 97%

Pre‐synaptic C‐terminal truncated tau is released from cortical synapses in Alzheimer's disease

Sokolow¹,

Henkins²,

Bilousova³

et al. 2015

Journal of Neurochemistry

116

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The microtubule-associated protein tau has primarily been associated with axonal location and function; however, recent work shows tau release from neurons and suggests an important role for tau in synaptic plasticity. In our study, we measured synaptic levels of total tau using synaptosomes prepared from cryopreserved human postmortem Alzheimer's disease (AD) and control samples. Flow cytometry data show that a majority of synaptic terminals are highly immunolabeled with the total tau antibody (HT7) in both AD and control samples. Immunoblots of synaptosomal fractions reveal increases in a 20 kDa tau fragment and in tau dimers in AD synapses, and terminal-specific antibodies show that in many synaptosome samples tau lacks a C-terminus. Flow cytometry experiments to quantify the extent of C-terminal truncation reveal that only 15-25% of synaptosomes are positive for intact C-terminal tau. Potassium-induced depolarization demonstrates release of tau and tau fragments from presynaptic terminals, with increased release from AD compared to control samples. This study indicates that tau is normally highly localized to synaptic terminals in cortex where it is well-positioned to affect synaptic plasticity. Tau cleavage may facilitate tau aggregation as well as tau secretion and propagation of tau pathology from the presynaptic compartment in AD.

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“…Therefore, tau‐induced decreases in REM and NREM sleep may directly affect amyloid AD pathology, interact with A β ‐induced sleep problems, and could play a role in worsening disease. In the brain interstitial fluid, levels of tau, like A β , are increased with elevated neuronal activity, suggesting that increased wakefulness may elevate tau secretion and disease spreading in tauopathies . Whether changes in sleep affect tau pathology directly, as has been seen with A β , remains to be studied .…”

Section: Discussionmentioning

confidence: 99%

Altered sleep and EEG power in the P301S Tau transgenic mouse model

Holth

Mahan

Robinson

et al. 2017

Ann Clin Transl Neurol

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ObjectiveSleep disturbances are prevalent in human tauopathies yet despite the importance of sleep, little is known about its relationship with tau pathology. Here, we investigate this interaction by analyzing sleep and tau pathology throughout tauopathy disease progression in P301S human tau transgenic mice.MethodsP301S and wild‐type mice were analyzed by electroencephalography (EEG)/electromyography at 3, 6, 9, and 11 months of age for sleep/wake time, EEG power, and homeostatic response. Cortical volume and tau pathology was also assessed by anti‐phospho‐tau AT8 staining.ResultsP301S tau mice had significantly decreased rapid eye movement (REM) sleep at 9 months of age and decreased REM and non‐REM (NREM) sleep as well as increased wakefulness at 11 months. Sleep loss was characterized by fewer wake, REM, and NREM bouts, increased wake bout duration, and decreased sleep bout duration. Decreased REM and NREM sleep was associated with increased brainstem tau pathology in the sublaterodorsal area and parafacial zone, respectively. P301S mice also showed increased EEG power at 6 and 9 months of age and decreased power at 11 months. Decreased EEG power was associated with decreased cortical volume. Despite sleep disturbances, P301S mice maintained homeostatic response to sleep deprivation.InterpretationOur results indicate that tau pathology is associated with sleep disturbances that worsen with age and these changes may be related to tau pathology in brainstem sleep regulating regions as well as neurodegeneration. Tau‐induced sleep changes could affect disease progression and be a marker for therapeutic efficacy in this and other tauopathy models.

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Neuronal activity regulates extracellular tau in vivo

Cited by 54 publications

References 12 publications

Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression

Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression

Pre‐synaptic C‐terminal truncated tau is released from cortical synapses in Alzheimer's disease

Altered sleep and EEG power in the P301S Tau transgenic mouse model

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