Propagation of Tau aggregates
© The Author(s). 2017
Received: 3 May 2017
Accepted: 17 May 2017
Published: 30 May 2017
Since 2009, evidence has accumulated to suggest that Tau aggregates form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of Tau aggregates is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformation in a protein of the same kind, initiating a self-amplifying cascade. In addition, prion-like encompasses the release of protein aggregates from brain cells and their uptake by neighbouring cells. In mice, the intracerebral injection of Tau inclusions induced the ordered assembly of monomeric Tau, followed by its spreading to distant brain regions. Short fibrils constituted the major species of seed-competent Tau. The existence of several human Tauopathies with distinct fibril morphologies has led to the suggestion that different molecular conformers (or strains) of aggregated Tau exist.
Common human neurodegenerative diseases are characterized by the presence of abundant ordered assemblies with the properties of amyloid fibrils [1, 2]. These structures are typically unbranched and 10–20 nm in diameter; they are composed of β-strands running perpendicular to the fibre axis and β-sheets running parallel to the long axis of the fibrils. Each inclusion has a single protein as its major component, with Aβ, Tau and α-Synuclein being the most commonly involved. These proteins undergo a transformation from a soluble to an insoluble filamentous state, with a number of intermediates. The majority of neurodegenerative diseases is defined by one type of inclusion. Alzheimer’s disease (AD), the most prevalent, is characterized by two types of abundant inclusions, Aβ deposits and Tau assemblies.
Most cases of disease are sporadic, but a small percentage is inherited, often in a dominant manner. Inherited cases are caused by mutations in the genes encoding the proteins that make up the inclusions, or proteins that increase their production. Mutations in MAPT, the Tau gene, give rise to an inherited form of frontotemporal dementia and parkinsonism with abundant filamentous Tau inclusions in brain .
From genetic data, it is known that a dysfunction of the amyloid precursor protein (APP) initiates the disease process in familial AD . The same may be true of sporadic AD. However, it is also clear that pathological changes in Tau correlate better with nerve cell dysfunction than Aβ deposits [5, 6]. Moreover, a close relationship between tau inclusions and nerve cell loss is well established in hippocampus and cerebral cortex . Furthermore, it remains to be shown how changes in APP can cause neurotoxicity related to Tau aggregation.
For many years, cell autonomous mechanisms were believed to account for human neurodegenerative diseases, implying that the same aggregation events occur in brain cells, independently of neighbouring cells, resulting in degeneration. In post mortem brains, protein inclusions are present in thousands of cells. An alternative view is that the first inclusions form in a small number of cells, from where they propagate to normal cells through non-cell autonomous mechanisms and well-defined pathways depending on the underlying disease, resulting in degeneration.
Propagation of pathology is commonly called “prion-like”, referring to the intercellular spreading of protein aggregates. The acronym “prion” stands for “proteinaceous infectious particle”, reflecting intercellular propagation and interorganismal transmission . There is no evidence to suggest that Tauopathies can transfer between humans, hence the use of “prion-like.” Propagation of aggregates requires their release into the extracellular space, uptake by connected cells and seeded aggregation of soluble proteins. Studying the underlying mechanisms may lead to the identification of novel therapeutic targets.
The dwell time of Tau on individual microtubules is short and not significantly different between isoforms [13, 14]. Tau promoted microtubule assembly in the processes of differentiated PC12 cells, but it is not clear if it also stabilised microtubules. Its short dwell time on microtubules makes it possible for Tau to interact with additional molecules, such as actin and protein phosphatase 2A. In brain, Tau is subject to a number of post-translational modifications, including phosphorylation, acetylation, methylation, glycation, isomerisation, O-GlcNAcylation, nitration, sumoylation, ubiquitination and truncation .
Similar amounts of 3R and 4R Tau are expressed in the cerebral cortex of adults . In developing human brain, only the shortest Tau isoform is present. 3R, 4R and 5R Tau isoforms are found in the brains of adult chickens , whereas most adult rodents express only 4R Tau. What is conserved between species is the expression of one hyperphosphorylated 3R Tau isoform lacking amino-terminal inserts during vertebrate development. Similar repeats are present in the high-molecular weight proteins MAP2 and MAP4 [18, 19]. It has been suggested that MAP4 derives from a non-vertebrate ancestor, whereas MAP2 and Tau may have shared a more recent common ancestor . The genomes of Caenorhabditis elegans and Drosophila melanogaster each encode one protein with Tau-like repeats [21, 22].
Full-length Tau assembles into filaments through some of its repeats and adjoining sequences, with the amino-terminal half and most the carboxy-terminus forming the fuzzy coat [23–27]. Tau filaments from AD brain and those assembled from expressed protein have a cross-β structure characteristic of amyloid fibrils , with their cores consisting of approximately 90 amino acids. The core of Tau filaments overlaps with part of the region that binds to microtubules, implying that pathological assembly and physiological function are mutually exclusive.
Phosphorylation of Tau negatively regulates its ability to interact with microtubules and filamentous Tau is abnormally hyperphosphorylated . It remains to be seen if phosphorylation is a trigger for aggregation. Many publications equate Tau phosphorylation with aggregation. This may not be correct. It has for instance been shown that highly phosphorylated Tau forms in a reversible fashion during hibernation .
In AD, chronic traumatic encephalopathy (CTE), post-encephalitic parkinsonism and several other Tauopathies, all six isoforms are present in the disease filaments . In AD, filaments are either paired helical or straight, with both types sharing a common structural subunit . In other diseases-such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), globular glial Tauopathy (GGT) and aging-related Tau astrogliopathy (ARTAG)-only isoforms with 4R Tau are found in the filaments . In Pick’s disease (PiD), 3R Tau isoforms predominate in the inclusions . Unlike AD, these diseases lack Aβ deposits. The morphologies of Tau filaments in different diseases vary, even when they are made of the same isoforms.
It has been suggested that patients with AD-type neurofibrillary degeneration restricted to medial temporal lobe and hippocampus, who lack Aβ deposits, suffer from “primary age-related Tauopathy” (PART), a condition that differs from AD . It has also been proposed that tangle-only dementia (TD), a relatively rare form of dementia, represents a severe form of PART. However, the view that PART is different from AD has been challenged, because it is clinically and neuropathologically similar to what appear to be the early pathological stages of AD .
The interaction in vitro between unphosphorylated, full-length, recombinant Tau and some negatively charged compounds, such as sulphated glycosaminoglycans, results in filament assembly [34, 35]. Filaments are decorated by antibodies directed against the amino-and carboxy-termini of Tau, but not by an antibody directed against the repeats. These findings, which indicate that the repeat region is inaccessible to the antibody, are identical to those obtained in AD and other human Tauopathies . However, the mechanisms leading to filament formation inside human brain cells in sporadic Tauopathies remain to be identified. Heparin is probably not involved.
Hexapeptide sequences in R2 (amino acids 275–280, VQIINK) and R3 (amino acids 306–311, VQIVYK) are essential for Tau filament assembly [37, 38]. Microcrystals of a peptide comprising residues 306–311 formed steric zippers . In complex with microtubules, these hexapeptide sequences are in a hairpin conformation , consistent with the view that microtubule binding and pathological assembly of Tau are mutually exclusive. Residues 310–313 in Tau (YKPV) differ from the equivalent residues in MAP2 (TKKI). When the latter were changed to YKPV, MAP2c also assembled into filaments . The longest human brain Tau isoform (2N4R, 441 amino acids) contains cysteines in R2 (residue 291) and R3 (residue 322). Intra-and intermolecular disulphide bonds may play a role in the assembly of 3R and 4R Tau into filaments.
Genetics of MAPT
The link between Tau dysfunction and neurodegeneration was established through human genetics. In June 1998, mutations in MAPT were reported in a dominantly inherited form of frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 [42–44]. Fifty-nine pathogenic MAPT mutations had been identified by January 2017 (Fig. 1b). Behavioural symptoms are the most common clinical sign. However, language disturbances are sometimes seen, as are signs of parkinsonism and motor neuron disease. The ages of onset are variable, but can be as early as in the third decade. MAPT mutations are always associated with abundant Tau inclusions in nerve cells or in both nerve cells and glial cells . By electron microscopy, Tau filament morphologies vary .
Mutations in MAPT account for around 5% of cases of FTD. They are concentrated in exons 9–12 (encoding R1-R4) and the introns flanking exon 10, and can be divided into those with a primary effect at the protein level and those affecting the alternative splicing of Tau pre-mRNA (Fig. 1). Mutations that act at the protein level change or delete single amino acids, reducing the ability of Tau to interact with microtubules. Some mutations also promote the assembly of Tau into filaments. Mutations with a primary effect at the RNA level are intronic or exonic and increase the alternative mRNA splicing of exon 10 of MAPT. This affects the ratio of 3R to 4R isoforms, resulting in the relative overproduction of 4R Tau, and its assembly into filaments. In neurons derived from induced pluripotent stem cells of patients with intronic MAPT mutations, 4R Tau was expressed during development, unlike what happens normally [46, 47].
Aggregated Tau can show different isoform patterns, depending on the MAPT mutations . Mutations V337M in exon 12 and R406W in exon 13 give rise to insoluble Tau bands of 60, 64 and 68 kDa and a weaker band of 72 kDa. Following dephosphorylation, six bands are present that align with recombinant Tau, like what is seen in AD. The brains of many individuals with MAPT mutations in exons 9–13 (K257T, L266V, ΔK280, S305N, G272V, L315R, S320F, S320Y, P332S, Q336H, Q336R, K369I, E372G and G389R) are characterized by abundant Pick bodies made predominantly of 3R Tau. As in sporadic PiD, insoluble Tau shows strong bands of 60 and 64 kDa. However, in most cases, variable amounts of the 68 and 72 kDa bands are also observed. A third pattern is characteristic of MAPT mutations that affect the alternative mRNA splicing of exon 10 (intronic mutations and exonic mutations N279K, L284L, L284R, ΔN296, N296D, N296H, N296N, S305I, S305N and S305S). Insoluble Tau runs as two strong bands of 64 and 68 kDa and a weaker band of 72 kDa; following dephosphorylation, three bands are present that align with recombinant 4R Tau (isoforms of 383, 412 and 441 amino acids). A similar pattern of pathological Tau bands is observed for mutations in exon 10, such as P301L, which have their primary effects at the protein level. Aggregation of 4R Tau has also been described for mutations I260V in exon 9, K317N in exon 11, E342V in exon 12 and N410H in exon 13, showing that it is possible to alter 3R and 4R Tau mRNAs through mutations located outside exon 10.
In populations of European descent, MAPT is characterised by two haplotypes resulting from a 900 kb inversion (H1) or non-inversion (H2) polymorphism . Inheritance of H1 is a risk factor for PSP, CBD and Parkinson’s disease (PD) . This has been confirmed in genome-wide association studies. The association with PD is particularly surprising, since PD is not characterised by the presence of Tau inclusions.
For PSP and CBD, an association has also been found with an allele at the MOBP/SLC25A38 locus, which results in elevated levels of appoptosin, a protein that activates caspase-3, which can cleave Tau . This may result in increased aggregation of 4R Tau. The association of H1 with PSP had a higher odds ratio than that between APOEε4/ε4 and AD . APOEε4 is the major risk factor allele for late-onset AD . H2 is associated with increased expression of exon 3 of MAPT in grey matter, suggesting that inclusion of exon 3 is protective . Reduced expression of 1N4R has also been associated with H2 . Tau isoforms containing exons 2 and 10 promote aggregation, whereas exon 3-containing isoforms are inhibitory .
Even though all six Tau isoforms form paired helical and straight filaments, there are no known mutations in MAPT that give rise to AD. Tau with an A152T substitution has been reported to be a risk factor for AD, as well as for PSP, CBD and unusual Tauopathies ([56–58], but see also ).
Propagation of TAU aggregates
Uptake of ordered Tau assemblies depends on heparan sulphate proteoglycans at the cell surface and may occur through macropinocytosis, at least in cultured cells . The seeds probably escape from endosomal vesicles and induce the assembly of cytoplasmic Tau. Following assembly, Tau aggregates are released from cells through ill-defined mechanisms. Intracellular Tau could transfer between cells through tunnelling nanotubes. Alternatively, it could be released into the extracellular space, either freely or inside vesicles. Antibodies may be able to target extracellular Tau aggregates, provided they are not transported in vesicles. Passive immunisation with anti-Tau antibodies has been shown to reduce the amounts of aggregated, hyperphosphorylated Tau in transgenic mice [64–66]. Similarly, antisense oligonucleotides reduced Tau pathology . The aggregation of Tau is known to be concentration-dependent. Tau assemblies can enter cells, where they are detected and neutralised via a danger response mediated by bound anti-Tau antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21) .
Microglial cells have been reported to promote Tau propagation through exosome-dependent mechanisms . A separate study concluded that Tau was released from cells through an exosome-independent pathway that required heat shock cognate 70, its co-chaperone DnaJ and synaptosomal-associated protein 23 . This work probably described the release of aggregation-incompetent soluble tau. By contrast, optogenetic and chemogenetic approaches have shown that an increase in neural activity can accelerate Tauopathy in transgenic mice .
Tau seeds do not need to be phosphorylated, even though seeded Tau aggregates are hyperphosphorylated . Tau assemblies may grow by incorporating unphosphorylated Tau which then undergoes a conformational change and becomes hyperphosphorylated. It remains to be seen if phosphorylation of Tau can influence seeded aggregation.
The intracerebral injection of brain extracts from mice expressing human P301S Tau with inclusions into mice transgenic for wild-type human Tau lacking inclusions (line ALZ17) induced the assembly of wild-type Tau into filaments and its spreading to distant brain regions . No inclusions formed when Tau was depleted from the extracts prior to injection. Aggregated recombinant human Tau also induced inclusion formation, but with a lower efficiency than aggregated Tau from transgenic mouse brain [72, 73]. Similar differences have been described for prions, Aβ, α-synuclein and reactive serum amyloid A assemblies. Recombinant Tau aggregates were more resistant to disaggregation by guanidine hydrochloride and digestion by proteinase K than Tau aggregates from transgenic mouse brain, consistent with the view that more stable aggregates possess lower seeding activity .
Distinct conformations of assembled Tau accounted for differences in seeding potency. Tau filaments formed from recombinant P301S Tau following seeding with aggregated Tau from transgenic mouse brain (in the absence of heparin) showed resistance to guanidine hydrochloride, which was similar to that of Tau seeds from the brains of mice transgenic for human P301S Tau. The seeding potency of Tau filaments was like that of brain-derived aggregated Tau.
When presymptomatic P301S Tau transgenic mice were injected intracerebrally with brain extracts from symptomatic animals, Tau inclusions formed rapidly at the injection sites . Contralateral and caudo-rostral propagation was evident in nuclei with strong afferent and efferent connections to the injection sites, indicating that the spread of pathology was dependent on connectivity, not proximity.
The intraperitoneal injection of brain extracts from symptomatic P301S Tau transgenic mice into presymptomatic mice promoted the formation of cerebral Tau inclusions . Aggregated Tau can thus promote inclusion formation in the central nervous system of transgenic mice following peripheral administration. Similar findings have been reported for prions, assembled Aβ and assembled α-synuclein.
Strains of aggregated TAU
In 2013, we showed that the intracerebral injection of brain homogenates from humans with pathologically confirmed Tauopathies led to the formation of neuronal and glial Tau inclusions in ALZ17 mice . Inclusions formed after inoculation of brain homogenates from all cases of AD, TD, PiD, AGD, PSP and CBD. Brain homogenates from patients with AGD, PSP and CBD produced lesions similar to those of the human disorders. With the exception of PiD (3R), the inclusions of the Tauopathies used were made of either 4R Tau (AGD, PSP and CBD) or a mixture of 3R and 4R Tau (AD and TD).
Injection of PSP homogenates into ALZ17 mice gave rise to silver-positive neuronal and glial Tau aggregates; the latter were similar to tufted astrocytes, the hallmark lesion of PSP. The injection of CBD homogenates produced neuronal inclusions and silver-positive structures reminiscent of astrocytic plaques. With AGD homogenates, argyrophilic grains and silver-negative astrocytic Tau inclusions were seen, like in the human disease. With the exception of PiD, Tau inclusions propagated over time to connected brain regions. Similar inclusions, but fewer in number, formed after the intracerebral injection into non-transgenic mice of brain homogenates from human Tauopathies. Similar findings have been reported by others following the injection of AD brain extracts into wild-type mice [78, 79].
These findings were complemented by studies in HEK293 cells that had been stably transfected with part of 4R Tau (residues 244–372) with mutations P301L and V337M fused to YFP . When exposed to Tau seeds, mutant 4R Tau aggregated. Two Tau strains were isolated, based on distinct inclusion morphologies, as well as different biochemical and structural characteristics. Inoculation of these assemblies into the hippocampus of young mice transgenic for human mutant P301S tau (line PS19) induced Tau pathologies that were stable through serial transmission. When HEK cells expressing mutant 4R Tau were seeded with homogenates from these brains, inclusions formed that were identical to those present initially. In subsequent work, another 18 Tau strains were isolated . It remains to be seen how these strains relate to the molecular conformers of aggregated Tau that are characteristic of human Tauopathies.
Induced Tau pathology propagated serially, when brain homogenates from ALZ17 mice that had received bilateral injections of brain extracts from human P301S Tau transgenic mice 18 months earlier, were injected into 3-month-old ALZ17 mice . In a different experiment, homogenates were prepared from the brains of non-transgenic mice that had been injected bilaterally with AGD brain homogenates 18 months earlier. Twelve months after the intracerebral injection of these homogenates into ALZ17 mice, many neuropil threads and Tau aggregates were present at the injection sites.
Overexpression of full-length human wild-type 2N3R tau or mutant P301S tau resulted in seeded aggregation upon exposure to AD seeds [68, 78]. Similar findings were obtained when primary neurons from wild-type mice were treated with Tau filaments from AD brain . Seeded aggregation of mutant 4R Tau (244–372) was also observed upon exposure to CTE, PSP, CBD and AGD brain extracts . However, these findings were at the light microscopic level. The resulting Tau filament morphologies are not known. Different strains of aggregated Tau may well exist, but additional work is required. In particular, it will be important to determine if Tau strains from human brain possess unique structural features.
The ordered assembly of Tau represents the gain of toxic function that causes human Tauopathies. Downstream of assembly, Tau propagation and neurodegeneration take place. Small Tau fibrils are the major species responsible for propagation. The molecular Tau species responsible for neurodegeneration remain to be identified.
Availability of data and supporting materials
Both authors contributed equally to the writing.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Goedert M. Alzheimer’s and Parkinson’s diseases: the prion concept in relation to assembled Aβ, tau and α-synuclein. Science. 2015;349:1255555.View ArticlePubMedGoogle Scholar
- Arendt T, Stieler JT, Holzer M. Tau and tauopathies. Brain Res Bull. 2016;126:238–92.View ArticlePubMedGoogle Scholar
- Ghetti B, Oblak AL, Boeve BF, Johnson KA, Dickerson BC, Goedert M. Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol Appl Neurobiol. 2015;41:24–46.View ArticlePubMedPubMed CentralGoogle Scholar
- Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608.View ArticlePubMedPubMed CentralGoogle Scholar
- Wilcock GK, Esiri MM. Plaques, tangles and dementia. A quantitative study. J Neurol Sci. 1982;56:343–56.View ArticlePubMedGoogle Scholar
- Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362–81.View ArticlePubMedPubMed CentralGoogle Scholar
- Bondareff W, Mountjoy CQ, Roth M, Hauser DL. Neurofibrillary degeneration and neuronal loss in Alzheimer’s disease. Neurobiol Aging. 1989;10:709–15.View ArticlePubMedGoogle Scholar
- Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. 1982;216:136–44.View ArticlePubMedGoogle Scholar
- Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron. 1989;3:519–26.View ArticlePubMedGoogle Scholar
- Goedert M, Spillantini MG, Crowther RA. Cloning of a big tau microtubule-associated protein tau characteristic of the peripheral nervous system. Proc Natl Acad Sci U S A. 1992;89:1983–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Couchie D, Mavilia C, Georgieff IS, Liem RK, Shelanski ML, Nunez J. Primary structure of high molecular weight tau present in the peripheral nervous system. Proc Natl Acad Sci U S A. 1992;89:4378–81.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17:5–21.View ArticlePubMedGoogle Scholar
- Janning D, Igaev M, Sündermann F, Bruhmann J, Beutel O, Heinisch JJ, Bakota L, Piehler J, Junge W, Brandt R. Single-molecule tracking of tau reveals fast kiss-and-hop interaction with microtubules in living neurons. Mol Biol Cell. 2014;25:3541–51.View ArticlePubMedPubMed CentralGoogle Scholar
- Niewidok B, Igaev M, Sündermann F, Janning D, Bakota L, Brandt R. Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau’s interaction with microtubules in axon-like processes. Mol Biol Cell. 2016;27:3537–49.View ArticlePubMedPubMed CentralGoogle Scholar
- Morris M, Knudsen GM, Maeda S, Trinidad JC, Ioanoviciu A, Burlingame AL, Mucke L. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci. 2015;18:1183–9.View ArticlePubMedGoogle Scholar
- Goedert M, Jakes R. Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J. 1990;9:4225–30.PubMedPubMed CentralGoogle Scholar
- Yoshida H, Goedert M. Molecular cloning and functional characterization of chicken brain tau: isoforms with up to five tandem repeats. Biochemistry. 2002;41:15203–11.View ArticlePubMedGoogle Scholar
- Aizawa H, Emori Y, Murofushi H, Kawasaki H, Sakai H, Suzuki K. Molecular cloning of a ubiquitously distributed microtubule-associated protein with Mr 190,000. J Biol Chem. 1990;265:13849–55.PubMedGoogle Scholar
- Lewis SA, Wang D, Cowan NJ. Microtubule-associated protein MAP2 shares a microtubule binding motif with tau protein. Science. 1988;242:936–9.View ArticlePubMedGoogle Scholar
- Sündermann F, Fernandez M-P, Morgan RO. An evolutionary roadmap to the microtubule-associated protein MAP Tau. BMC Genomics. 2016;17:264.View ArticlePubMedPubMed CentralGoogle Scholar
- Goedert M, Baur CP, Ahringer J, Jakes R, Hasegawa M, Spillantini MG, Smith MJ, Hill F. PTL-1, a microtubule-associated protein with tau-like repeats from the nematode Caenorhabditis elegans. J Cell Sci. 1996;109:2661–72.PubMedGoogle Scholar
- Heidary G, Fortini ME. Identification and characterization of the Drosophila tau homolog. Mech Dev. 2001;108:171–8.View ArticlePubMedGoogle Scholar
- Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A. 1988;85:4051–5.View ArticlePubMedPubMed CentralGoogle Scholar
- Wischik CM, Novak M, Thogersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988;85:4506–10.View ArticlePubMedPubMed CentralGoogle Scholar
- Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988;85:4884–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Kondo J, Honda T, Mori H, Hamada Y, Miura R, Ogawara M, Ihara Y. The carboxyl third of tau is tightly bound to paired helical filaments. Neuron. 1988;1:827–34.View ArticlePubMedGoogle Scholar
- Wegmann S, Medalsy ID, Mandelkow E, Müller DJ. The fuzzy coat of pathological human tau fibrils is a two-layered polyelectrolyte brush. Proc Natl Acad Sci U S A. 2013;110:E313–21.View ArticlePubMedGoogle Scholar
- Berriman J, Serpell LC, Oberg KA, Fink AL, Goedert M, Crowther RA. Tau filaments from human brain and from in vitro assembly of recombinant proteins show cross-beta structure. Proc Natl Acad Sci U S A. 2003;100:9034–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Iqbal K, Liu F, Gong CX. Tau and neurodegenerative disease: the story so far. Nat Rev Neurol. 2016;12:15–27.View ArticlePubMedGoogle Scholar
- Arendt T, Stieler J, Strijkstra AM, Hut RA, Rüdiger J, Van der Zee EA, Harkany T, Holzer M, Härtig W. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci. 2003;23:6972–81.PubMedGoogle Scholar
- Crowther RA. Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc Natl Acad Sci U S A. 1991;88:2288–92.View ArticlePubMedPubMed CentralGoogle Scholar
- Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alazuloff I, Arnold SE, Attems J, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Gearing M, Grinberg LT, Hof PR, Hyman BT, Jellinger K, Jicha GA, Kovacs GG, Knopman DS, Kofler J, Kukull WA, Mackenzie IR, Masliah E, McKee A, Montine TJ, Murray ME, Neltner JH, Santa-Maria I, Seeley WW, Serrano-Pozo A, Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso JC, Vonsattel JP, White CL, Wisniewski T, Woltier RL, Yamada M, Nelson PT. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 2014;128:755–66.View ArticlePubMedPubMed CentralGoogle Scholar
- Duyckaerts C, Braak H, Brion JP, Buée L, Del Tredici K, Goedert M, Halliday G, Neumann M, Spillantini MG, Tolnay M, Uchihara T. PART is part of Alzheimer disease. Acta Neuropathol. 2015;129:749–56.View ArticlePubMedPubMed CentralGoogle Scholar
- Goedert M, Jakes R, Spillantini MG, Hasegawa M, Smith MJ, Crowther RA. Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature. 1996;383:550–3.View ArticlePubMedGoogle Scholar
- Pérez M, Valpuesta JM, Medina M, De Garcini EM, Avila J. Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction. J Neurochem. 1996;67:1183–90.View ArticlePubMedGoogle Scholar
- Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 1992;8:159–68.View ArticlePubMedGoogle Scholar
- Von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif (306-VQIVYK-311) forming beta structure. Proc Natl Acad Sci U S A. 2000;97:5129–34.View ArticleGoogle Scholar
- Von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM, Mandelkow E. Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta structure. J Biol Chem. 2001;276:48165–74.View ArticleGoogle Scholar
- Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJ, McFarlane HT, Madsen AO, Riekel C, Eisenberg D. Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature. 2007;447:453–7.View ArticlePubMedGoogle Scholar
- Kadavath H, Jaremko M, Jaremko L, Biernat J, Mandelkow E, Zweckstetter M. Folding of the tau protein on microtubules. Angew Chem Int Ed. 2015;54:10347–51.View ArticleGoogle Scholar
- Xie C, Soeda Y, Shinzaki Y, In Y, Tomoo K, Ihara Y, Miyasaka T. Identification of key amino acids responsible for the distinct aggregation properties of microtubule-associated protein 2 and tau. J Neurochem. 2015;135:19–26.View ArticlePubMedPubMed CentralGoogle Scholar
- Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998;43:815–25.View ArticlePubMedGoogle Scholar
- Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaf E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski JQ, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JBJ, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5′-splice site mutations in tau with the inherited demenmtia FTDP-17. Nature. 1998;393:702–5.View ArticlePubMedGoogle Scholar
- Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998;95:7737–41.View ArticlePubMedPubMed CentralGoogle Scholar
- Crowther RA, Goedert M. Abnormal tau-containing filaments in neurodegenerative diseases. J Struct Biol. 2000;130:271–9.View ArticlePubMedGoogle Scholar
- Iovino M, Agathou S, González-Rueda A, Del Castillo-Herrera M, Borroni B, Alberici A, Lynch T, O’Dowd S, Geti I, Gaffney D, Vallier L, Paulsen O, Káradóttir RT, Spillantini MG. Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain. 2015;138:3345–59.View ArticlePubMedPubMed CentralGoogle Scholar
- Sposito T, Preza E, Mahoney CJ, Setó-Salvia N, Ryan NS, Morris HR, Arber C, Devine MJ, Goulden H, Warner TT, Bushell TJ, Zagnoni M, Kunath T, Livesey FJ, Fox NC, Rossor MN, Hardy J, Wray S. Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum Mol Genet. 2015;24:5260–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Goedert M, Eisenberg DS, Crowther RA. Propagation of Tau aggregates and neurodegeneration. Annu Rev Neurosci 2017;40:189–210.Google Scholar
- Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J, Baker A, Jonasdottir A, Ingason A, Gudnadottir VG, Desnica N, Hicks A, Gylfason A, Gudbjartsson DF, Jonsdottir GM, Sainz J, Agnarsson K, Birgisdottir B, Ghosh S, Olafsdottir A, Cazier JB, Kristjansson K, Frigge ML, Thorgeirsson TE, Gulcher JR, Kong A, Stefansson K. A common inversion under selection in Europeans. Nat Genet. 2005;37:129–37.View ArticlePubMedGoogle Scholar
- Zhao Y, Tseng I-C, Heyser CJ, Rockenstein E, Mante M, Adame A, Zheng Q, Huang T, Wang X, Arslan PE, Chakrabarty P, Wu C, Bu G, Mobley WC, Y-w Z, St George-Hyslop P, Masliah E, Fraser PK, Xu H. Appoptosin-mediated caspase cleavage of tau contributes to progressive supranuclear palsy pathogenesis. Neuron. 2015;87:963–75.View ArticlePubMedPubMed CentralGoogle Scholar
- Höglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wamng LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Müller U, Schellenberg GD. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011;43:699–705.View ArticlePubMedPubMed CentralGoogle Scholar
- Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3.View ArticlePubMedGoogle Scholar
- Caffrey TM, Joachim C, Wade-Martins R. Haplotype-specific expression of the N-terminal exon 2 and 3 at the human MAPT locus. Neurobiol Aging. 2008;29:1923–9.View ArticlePubMedGoogle Scholar
- Valenca GT, Srivastava GP, Oliveira-Filho J, White CC, Yu L, Schneider JA, Buchman AS, Shulman JM, Bennett DA, Jager PL. The role of MAPT haplotype H2 and isoform 1 N/4R in parkinsonism of older adults. PLoS One. 2016;11:e0157452.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhong Q, Condon EE, Nagaraja HN, Kuret J. Tau isoform composition influences rate and extent of filament formation. J Biol Chem. 2012;287:20711–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Kovacs GG, Wöhrer A, Ströbel T, Botond G, Attems J, Budka H. Unclassifiable tauopathy associated with an A152T variation in MAPT exon 7. Clin Neuropathol. 2011;30:3–10.View ArticlePubMedGoogle Scholar
- Kara E, Ling H, Pittman AM, Shaw K, de Silva R, Simone R, Holton JL, Warren JD, Rohrer JD, Xiromerisiou G, Lees A, Hardy J, Houlden H, Revesz T. The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological features. Neurobiol Aging. 2012;33:2231.e7–e14.View ArticleGoogle Scholar
- Coppola G, Chinnathambi S, Lee JJ, Dombroski BA, Baker MC, Soto-Ortolazo AI, Lee SE, Klein E, Huang AY, Sears R, Lane JR, Karydas AM, Kenet RO, Biernat J, Wanf L-S, Cotman CW, DeCarli CS, Levey AI, Ringman JM, Mendez MF, Chui HC, Le Ber I, Brice A, Lupton MK, Preza E, Lovestone S, Powell J, Graff-Radford N, Petersen RC, Boeve BF, Lippa CF, Bigio EH, Mackenzie I, Finger E, Kertesz A, Caselli RJ, Gearing M, Juncos JL, Ghetti B, Spina S, Bordelon YM, Tourtelotte WW, Frosch MP, Vonsattel JPG, Zarow C, Beach TG, Albin RL, Lieberman AP, Lee VMY, Trojanowski JQ, Van Deerlin VM, Bird TD, Galasko DR, Masliah E, White CL, Troncoso JC, Hannequin D, Boxer AL, Geschwind MD, Kumar S, Mandelkow EM, Wszolek ZK, Uitti RJ, Dickson DW, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Ross OA, Rademakers R, Schellenberg GD, Miller BL, Mandelkow E, Geschwind DH. Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer’s diseases. Hum Mol Genet. 2012;21:3500–12.View ArticlePubMedPubMed CentralGoogle Scholar
- Pastor P, Moreno F, Clarimón J, Ruiz A, Combarros O, Calero M, López de Munain A, Bullido MJ, de Pancorbo MM, Carro E, Antonell A, Coto E, Ortega-Cubero S, Hernandez I, Tárraga L, Boada M, Lleó A, Dois-Icardo O, Kulisevsky J, Vázquez-Higuera JL, Infante J, Rábano A, Fernández-Blázquez MA, Valenti M, Indakoetxea B, Barandiarán M, Gorostidin A, Frank-Garcia A, Sastre I, Lorenzo E, Pastor MA, Elcoroaristizabal X, Lennarz M, Maier W, Rámirez A, Serrano-Rios M, Lee SE, Sánchez-Juan P. MAPT H1 haplotype is associated with late-onset Alzheimer’s disease risk in APOEε4 noncarriers: results from the Dementia Genetics Spanish Consortium. J Alzheimer’s Dis. 2016;49:343–52.View ArticleGoogle Scholar
- Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11:909–13.View ArticlePubMedPubMed CentralGoogle Scholar
- Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009;284:12845–52.View ArticlePubMedPubMed CentralGoogle Scholar
- Falcon B, Cavallini A, Angers R, Glover S, Murray TK, Barnham L, Jackson S, O’Neill MJ, Isaacs AM, Hutton ML, Szekeres PG, Goedert M, Bose S. Conformation determines the seeding potencies of native and recombinant tau aggregates. J Biol Chem. 2015;290:1049–65.View ArticlePubMedGoogle Scholar
- Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, Kotzbauer PT, Miller TM, Papy-Garcia D, Diamond MI. Heparan sulphate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013;110:E3138–47.View ArticlePubMedPubMed CentralGoogle Scholar
- Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, Buckner N, Hanmer J, Davies P, O’Neill MJ, Hutton ML, Citron M. Passive immunization with anti-tau antibodies in two transgenic models. J Biol Chem. 2011;286:34457–67.View ArticlePubMedPubMed CentralGoogle Scholar
- Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80:402–14.View ArticlePubMedPubMed CentralGoogle Scholar
- Sankaranarayanan S, Barten DM, Vana L, Devidze N, Yang L, Cadelina G, Hoque N, DeCarr L, Keenan S, Lin A, Cao Y, Snyder B, Zhang B, Nitla M, Hirschfeld G, Barrezueta N, Polson C, Wes P, Rangan VS, Cacace A, Albright CF, Meredith J, Trojanowski JQ, Lee VMY, Brunden KR, Ahlijanian M. Passive immunization with phosphor-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS One. 2015;10:e0l25614.Google Scholar
- DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, Chen G, Shen T, Tran H, Nichols B, Zanardi TA, Kordasiewicz HB, Swayze EE, Bennett CF, Diamond MI, Miller TM. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Science Transl Med. 2017;9:eaag0481.View ArticleGoogle Scholar
- McEwan WA, Falcon B, Vaysburd M, Clift D, Oblak AL, Ghetti B, Goedert M, James LC. Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. Proc Natl Acad Sci U S A. 2017;113:E8187–96.Google Scholar
- Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18:1584–93.View ArticlePubMedPubMed CentralGoogle Scholar
- Fontaine SN, Zheng D, Sabbagh JJ, Martin MD, Chaput D, Darling A, Trotter JH, Stothert AR, Nordhues BA, Lussier A, Baker J, Shelton L, Kahn M, Blair LJ, Stevens SM, Dickey CA. DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins. EMBO J. 2016;35:1537–49.View ArticlePubMedGoogle Scholar
- Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, Sanders DW, Cook C, Fu H, Boonen RA, Herman M, Nahmani E, Emrani S, Figueroa YH, Diamond MI, Clelland CL, Wray S, Duff KE. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016;19:1085–92.View ArticlePubMedPubMed CentralGoogle Scholar
- Clavaguera F, Lavenir I, Falcon B, Frank S, Goedert M, Tolnay M. “Prion-like” template misfolding in tauopathies. Brain Pathol. 2013;23:342–9.View ArticlePubMedGoogle Scholar
- Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VMY. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci. 2013;33:1024–37.View ArticlePubMedPubMed CentralGoogle Scholar
- Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, Parhizkar S, Ward MA, Cavallini A, Jackson S, Bose S, Clavaguera F, Tolnay M, Lavenir I, Goedert M, Hutton ML, O’Neill MJ. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 2014;127:667–83.View ArticlePubMedPubMed CentralGoogle Scholar
- Clavaguera F, Hench J, Lavenir I, Schweighauser G, Frank S, Goedert M, Tolnay M. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 2014;127:299–301.View ArticlePubMedGoogle Scholar
- Jackson SJ, Kerridge C, Cooper J, Cavallini A, Falcon B, Cella CV, Landi A, Szekeres PG, Murray TK, Ahmed Z, Goedert M, Hutton M, O’Neill MJ, Bose S. Short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. J Neurosci. 2016;36:762–72.View ArticlePubMedPubMed CentralGoogle Scholar
- Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Probst A, Winkler DT, Reichwald J, Staufenbiel M, Ghetti B, Goedert M, Tolnay M. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013;110:9535–40.View ArticlePubMedPubMed CentralGoogle Scholar
- Audouard E, Houben S, Masaracchia C, Yilmaz Z, Suain V, Authelet M, De Decker R, Buée L, Boom A, Leroy K, Ando K, Brion JP. High-molecular weight paired helical filaments from Alzheimer brain induces seeding of wild-type mouse tau into an argyrophilic 4R tau pathology in vivo. Am J Pathol. 2016;186:2709–22.View ArticlePubMedGoogle Scholar
- Guo JL, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B, Gathagan RJ, Iba M, McBride JD, Trojanowski JQ, Lee VMY. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med. 2016;213:2635–54.View ArticlePubMedPubMed CentralGoogle Scholar
- Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirhaba H, Li A, Barker SJ, Foley AC, Thorpe JR, Serpell LC, Miller TM, Grinberg LT, Seeley WW, Diamond MI. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82:1271–88.View ArticlePubMedPubMed CentralGoogle Scholar
- Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM, Miller TM, Diamond MI. Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron. 2016;92:796–812.View ArticlePubMedGoogle Scholar
- Woerman AL, Aoyagi A, Patel S, Kazmi SA, Lobach I, Grinberg LT, McKee AC, Seeley WW, Olson SH, Prusiner SB. Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc Natl Acad Sci U S A. 2016;113:E8187–96.View ArticlePubMedGoogle Scholar