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Supplementary information S1 (box) | Additional major findings in tau research
Self-assembly of tau into filaments by dialysis from 6 M urea is demonstrated1
Ubiquitination of tau in Alzheimer neurofibrillary tangles is reported2,3
Localization of tau in the somatodendritic compartment is shown by in situ
hybridization in normal and ADbrains4
1992–1993
Isolation of tau protein kinase I (GSK-3β) and hyperphosphorylation of tau
by this kinase are described5–7
1994 Glycation of tau is found in PHFs8,9
1995 An overexpression transgenic mouse model displaying pretangle phenotype is
reported10
1996 Enzymatic dephosphorylation, especially with PP2A, is found to convert AD P-tau
into a seemingly normal protein that promotesmicrotubule assembly11
1996 Glycosylation of tau in PHFs is discovered12
1996 Tau assembly into filaments is reported to be facilitated by polyanions13,14
1997 AD P-tau is observed to bind MAP1 and MAP2 and depolymerize microtubules, but
this interaction does not result in formation of filaments15
1998 Combined activities of PDPKs and non-PDPKs are found to be involved in abnormal
hyperphosphorylation of tau16
1999 Generation of a transgenic mouse model with a neurodegenerative tauopathy
phenotype and tau pathology is reported18
2000 PP2A is identified as the major regulator of phosphorylation of tau18,19
2001 Aβ is found to enhance tau pathology in transgenic mice expressing mutated tau20,21
2002 Tau is found to be essential for Aβ-induced neurotoxicity22
2004 The FTDP-17 tau mutations are found to make tau a more favourable substrate for
abnormal hyperphosphorylation than normal protein23
2005 Reports of cloning of inhibitors 1 (I1PP2A) and 2 (I2PP2A) of PP2A from the human
brain, and regulation of PP2A activity towards hyperphosphorylated tau by these
inhibitors24
2005 Microtubule stabilizing compound is shown to offset loss of tau in a transgenic
mouse model of tauopathy25
2006 Tau is found to become a preferred substrate for hyperphosphorylation when it is
dissociated from microtubules and/or when it contains the amino-terminal inserts26
2006 Extracellular tau is found to be toxic to neuronal cells27
2007 A paper clip model of the conformation of tau is proposed28
2007 Involvement of protein kinases and phosphatases and phosphorylation sites in selfassembly of tau into PHFs and disruption of microtubules is established29
2008 Accumulation of tau truncated at Glu391 and at Asp421 is shown to directly
correlate with progression of AD30
2010 Phosphorylation of tau at Thr212, Thr231 and Ser262 combined is found to cause
neurodegeneration31
2010 Sodium selenate is shown to rescue tau pathology and behavioural deficits by
stabilizing PP2A tau complex in transgenic mice overexpressing mutated tau32
2014 Expression of I2CTF is found to produce both AD-type and ALS-type pathology and
clinical phenotypes in rats33
2014 Truncation of tau by asparaginylendopeptidase is found to result in a toxic fragment34
2015 Passive immunization targeting the amino-terminal domain of tau is shown to rescue
tau pathology and cognitive impairment in a transgenic mouse model of AD and
tauopathies35
1986
1987
1989
Abbreviations: Aβ, amyloid-β; AD, Alzheimer disease; ALS, amyotrophic lateral sclerosis;
FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; MAP,
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microtubule-associated protein; PDPKs, proline-directed protein kinases; PHFs, paired
helical filaments; PP2A, protein phosphatase 2A; P-tau, hyperphosphorylated tau.
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