Microtubule-associated protein tau. A component of Alzheimer paired helical filaments.

Grundke‐Iqbal, Inge; Iqbal, Khalid; Quinlan, M; Tung, Yunn Chyn; Zaidi, Mariem; Wiśniewski, H. M.

doi:10.1016/s0021-9258(17)38495-8

Cited by 1,523 publications

(170 citation statements)

References 33 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…It was also found to be stable when purified using TCA (data not shown) ( 62 ). Heat stability is an inherent property of tau as an aggregation-prone and intrinsically unstructured protein without a hydrophobic core ( 63 , 64 , 65 ) and is widely used as a method for separation of tau from other abundant proteins ( 2 , 63 , 64 ). In contrast to tau, other synaptic proteins were not heat stable.…”

Section: Discussionmentioning

confidence: 99%

Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia

Lemke

Melis

Lauer

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer’s disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that non-phosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, while endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilisation with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. Mass spectrometry corroborated that synaptosomal tau is non-phosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and non-phosphorylated state, and one that could have a direct impact on cognitive function.

show abstract

Section: Discussionmentioning

confidence: 99%

Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia

Lemke

Melis

Lauer

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Tau was first identified as a microtubule‐associated protein in the 1970s 1–4 . The protein received increasing attention after it was shown in 1986 that it is the major constituent of paired helical filaments (PHFs) and straight filaments (SFs) found in the brain of Alzheimer's disease (AD) patients 5–13 . In addition, mutations in tau were identified in patients that were diagnosed with frontotemporal dementia, indicating that tau is a disease‐causing agent 14–19 .…”

Section: Tau In Physiology and Pathologymentioning

confidence: 99%

“…The brains of AD patients are characterized by the presence of NFTs and NTs, intracellular inclusions composed of amyloid‐like fibrils of misfolded, hyperphosphorylated forms of tau 6,11,12,22 . NFTs and NTs accumulate in the neuronal somata and the dendrites, respectively 11,78 .…”

Section: Tau In Physiology and Pathologymentioning

confidence: 99%

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

et al. 2021

View full text Add to dashboard Cite

Biomolecular condensation via liquid–liquid phase separation (LLPS) of intrinsically disordered proteins/regions (IDPs/IDRs), with and without nucleic acids, has drawn widespread interest due to the rapidly unfolding role of phase‐separated condensates in a diverse range of cellular functions and human diseases. Biomolecular condensates form via transient and multivalent intermolecular forces that sequester proteins and nucleic acids into liquid‐like membrane‐less compartments. However, aberrant phase transitions into gel‐like or solid‐like aggregates might play an important role in neurodegenerative and other diseases. Tau, a microtubule‐associated neuronal IDP, is involved in microtubule stabilization, regulates axonal outgrowth and transport in neurons. A growing body of evidence indicates that tau can accomplish some of its cellular activities via LLPS. However, liquid‐to‐solid transition resulting in the abnormal aggregation of tau is associated with neurodegenerative diseases. The physical chemistry of tau is crucial for governing its propensity for biomolecular condensation which is governed by various intermolecular and intramolecular interactions leading to simple one‐component and complex multi‐component condensates. In this review, we aim at capturing the current scientific state in unveiling the intriguing molecular mechanism of phase separation of tau. We particularly focus on the amalgamation of existing and emerging biophysical tools that offer unique spatiotemporal resolutions on a wide range of length‐ and time‐scales. We also discuss the link between quantitative biophysical measurements and novel biological insights into biomolecular condensation of tau. We believe that this account will provide a broad and multidisciplinary view of phase separation of tau and its association with physiology and disease.

show abstract

“…Healthy neurons express robust levels of tau that localize to axonal microtubules for transport and stabilization (Kahlson and Colodner, 2015). In neurons of AD patients, tau becomes hyperphosphorylated, causing it to disassociate from the microtubule and form pathological aggregates that spread in a characteristic pattern, originating in the entorhinal cortex and locus coeruleus and progressing to the neocortex (Grundke-Iqbal et al, 1986;Braak and Braak, 1991;Hyman, 1997;Franzmeier et al, 2020). Healthy astrocytes express very low levels of tau (Müller et al, 1997;Kahlson and Colodner, 2015;Perea et al, 2019).…”

Section: Tau Internalization In Astrocytesmentioning

confidence: 99%

Astrocytic Propagation of Tau in the Context of Alzheimer's Disease

Fleeman

Proctor

2021

Front. Cell. Neurosci.

View full text Add to dashboard Cite

More than 6 million Americans are currently living with Alzheimer's disease (AD), and the incidence is growing rapidly with our aging population. Numerous therapeutics have failed to make it to the clinic, potentially due to a focus on presumptive pathogenic proteins instead of cell-type-specific signaling mechanisms. The tau propagation hypothesis that inter-neuronal tau transfer drives AD pathology has recently garnered attention, as accumulation of pathological tau in the brain has high clinical significance in correlating with progression of cognitive AD symptoms. However, studies on tau pathology in AD are classically neuron-centric and have greatly overlooked cell-type specific effects of tau internalization, degradation, and propagation. While the contribution of microglia to tau processing and propagation is beginning to be recognized and understood, astrocytes, glial cells in the brain important for maintaining neuronal metabolic, synaptic, trophic, and immune function which can produce, internalize, degrade, and propagate tau are understudied in their ability to affect AD progression through tau pathology. Here, we showcase evidence for whether tau uptake by astrocytes may be beneficial or detrimental to neuronal health and how astrocytes and their immunometabolic functions may be key targets for future successful AD therapies.

show abstract

Microtubule-associated protein tau. A component of Alzheimer paired helical filaments.

Cited by 1,523 publications

References 33 publications

Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia

Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

Astrocytic Propagation of Tau in the Context of Alzheimer's Disease

Contact Info

Product

Resources

About