Sites of phosphorylation in tau and factors affecting their regulation

Anderton, Brian H.; Betts, Joanna; Blackstock, Walter; Brion, Jean-Pierre; Chapman, Steve; Connell, James W.; Dayanandan, R; Gallo, Jean-Marc; Gibb, G M; Hanger, Diane P.; Hutton, Michael; Kardalinou, E; Leroy, Karelle; Lovestone, Simon; Mack, Till G. A.; Reynolds, C. Hugh; Slegtenhorst, Marjon van

doi:10.1042/bss0670073

Cited by 88 publications

(35 citation statements)

References 12 publications

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“…Tau hyperphosphorylation at Thr-212, Ser-202, Ser-396, and Ser-404 is found in paired helical filaments in AD brains (42,45). Reduction in A␤ 1-42 levels leads to GSK-3␤ inactivation and prevents Tau phosphorylation in vivo and in vitro (21,23).…”

Section: Discussionmentioning

confidence: 99%

β-Amyloid1–42 Gene Transfer Model Exhibits Intraneuronal Amyloid, Gliosis, Tau Phosphorylation, and Neuronal Loss

Rebeck

Hoe

Moussa

2010

Journal of Biological Chemistry

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Alzheimer disease is characterized by extracellular ␤-amyloid (A␤) plaques and intracellular inclusions containing neurofibrillary tangles of phospho-Tau and intraneuronal A␤ associated with neuronal cell death. We generated a novel gene transfer animal model using lentiviral A␤ 1-42 that resulted in intracellular but not extracellular A␤ accumulations in the targeted rat primary motor cortex. Expression of intracellular A␤ 1-42 led to pathological changes seen in human Alzheimer disease brains, including cell death, inflammatory signs, activation of two Tau kinases, and Tau hyperphosphorylation. Promoting clearance of lentiviral A␤ 1-42 reversed these effects, demonstrating that intraneuronal A␤ 1-42 is a toxic peptide that lies upstream of Tau modification. These studies reveal the role of intracellular A␤ 1-42 in a novel gene transfer animal model, which is a useful tool to study intraneuronal A␤ 1-42 -induced pathology in the absence of extracellular plaques. Targeted delivery of A␤ will allow speedy delineation of pathological mechanisms associated with specific neurodegenerative lesions. Alzheimer disease (AD)2 is the leading cause of dementia in the aging population. AD is characterized by widespread degeneration in the association cortices and the limbic system (1) accompanied by ␤-amyloid (A␤) deposition (2-4), the formation of intracellular neurofibrillary tangles of the Tau protein (5), and neuronal loss (6). A␤ 1-40 and A␤ 1-42 are produced intracellularly, and intraneuronal A␤ 1-42 accumulates in the brain of individuals with AD (7-11). Both intracellular A␤ and extracellular oligomeric A␤ have been implicated in AD pathology, but intracellular oligomeric species may act in the earlier stages of disease (12, 13). A␤ is produced intracellularly via the endosomal system and secretory pathways (14,15). In AD, endosomes in the pyramidal neurons are significantly bigger than control (16), and endocytic alterations can even happen before clinical symptoms and accumulation of extracellular A␤ deposits (17). In primary cultures of neurons overexpressing ␤-amyloid precursor protein, accumulation of intraneuronal A␤ induces neuronal apoptotic cell death (18). These findings suggest a crucial role for intracellular A␤ in the early stages of AD.Some studies showed that Tau is required for A␤ 1-42 to mediate detrimental effects, including toxicity in cell culture (19) and learning and memory impairments in amyloid precursor protein mice (20). Intracellular A␤ 1-42 accumulation precedes Tau pathology in triple transgenic mice exhibiting both plaque and tangle pathologies (13, 21), whereas ␤-amyloid pathology alone exacerbates Tau pathology (22). Removal of A␤ 1-42 significantly reduces Tau hyperphosphorylation in rodents (21, 23). These findings suggest a complex relationship between Tau and A␤ pathology in AD and other tauopathies.AD neuropathological changes also include astrogliosis and microglial cell proliferation (24 -27). Astrocytes and microglia are activated in areas of the brain affected by amyloid plaq...

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Section: Discussionmentioning

confidence: 99%

β-Amyloid1–42 Gene Transfer Model Exhibits Intraneuronal Amyloid, Gliosis, Tau Phosphorylation, and Neuronal Loss

Rebeck

Hoe

Moussa

2010

Journal of Biological Chemistry

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“…These two phosphomimics, both human 2N4R tau, simulate permanent phosphorylation at 18 and 27 phosphorylation sites, respectively, by mutation of serine or threonine residues to glutamate, which mimics the presence of a phosphate group (28). All the mutated sites are known to be present in PHF tau, and the majority are phosphorylated by GSK-3 in vitro (2,3,41). E18tau and E27tau mimic functional aspects of GSK-3-phosphorylated tau protein, including a reduced ability to promote microtubule assembly (28,42,43).…”

Section: Phosphomimic Tau Mutants Are Transported Faster Than Wild-tymentioning

confidence: 99%

Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin

et al. 2008

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Defective axonal transport has been proposed as an underlying mechanism that may give rise to neurodegeneration. We investigated the effect of phosphorylation on the axonal transport of tau, a neuronal protein that stabilizes microtubules and is hyperphosphorylated and mislocalized in Alzheimer's disease. We report here that specific inhibition of glycogen synthase kinase-3 (GSK-3) reduces tau phosphorylation and significantly decreases the overall rate of axonal transport of tau in rat cortical neurons. Tau mutants, with serine/threonine targets of GSK-3 mutated to glutamate to mimic a permanent state of phosphorylation, were transported at a significantly increased rate compared to wild-type tau. Conversely, tau mutants, in which alanine replaced serine/threonine to mimic permanent dephosphorylation, were transported at a decreased rate compared to wild-type tau. We also found that tau interacts with the light chain of kinesin-1 and that this is dependent on the phosphorylation state of tau. Tau phosphorylation by GSK-3 increased binding, and dephosphorylated tau exhibited a reduced association with kinesin-1. We conclude that GSK-3 phosphorylation of tau modulates its axonal transport by regulating binding to kinesin-1. Hyperphosphorylated tau in Alzheimer's disease appearing first in distal portions of axons may result from aberrant axonal transport of phosphorylated tau reported here.

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“…Tau hyperphosphorylation arises as a result of aberrant protein kinase and/or phosphatase activity and an increasing number of protein kinases have been shown to phosphorylate tau at epitopes of relevance to AD (Hanger et al 1992(Hanger et al , 2007Baumann et al 1993;Goedert et al 1997;Reynolds et al 1997;Anderton et al 2001;Guise et al 2001;Derkinderen et al 2005). In tau transgenic mice, specific and broad-range protein kinase inhibitors can lower abnormal tau phosphorylation and aggregation, and significantly reduce both neuronal degeneration (Noble et al 2005;Le Corre et al 2006) and behavioral deficits (Le Corre et al 2006).…”

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confidence: 99%

Kinase activities increase during the development of tauopathy in htau mice

Kelleher

Garwood

Hanger

et al. 2007

Journal of Neurochemistry

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Hyperphosphorylated tau aggregates are the core constituent of neurofibrillary tangles. Recent research has shown a division between the presence of tangles, neurodegeneration and subsequent memory impairment, raising the possibility that an earlier pre-aggregated form of tau may be toxic. To gain further insight into the relationship between abnormal forms of tau, we have analyzed pathological changes in tau during tauopathy development in tangle-forming transgenic mice. In addition, we have quantified changes in the endogenous levels of a panel of protein kinases. We show progressive increases in aggregated tau and disease-specific conformational change, with hyperphosphorylation occurring in an agedependent manner at specific sites. There were significant correlations between specific phosphorylation changes and amounts of aggregated tau and and abnormal tau conformations. Of the protein kinases tested, we found increases in phosphorylated (activated) p38 and the cyclin-dependent kinase-5 neuronal activators, p35 and p25, with aging, in the htau line, but not in non-tangle-forming control mice. Changes in tau kinases correlated with the amount of tau present in abnormal conformations and with insoluble tau in htau mice. These data suggest that cdk5 and p38 may be associated with pathological changes in wild-type human tau during the progressive development of tauopathy.

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Sites of phosphorylation in tau and factors affecting their regulation

Cited by 88 publications

References 12 publications

β-Amyloid1–42 Gene Transfer Model Exhibits Intraneuronal Amyloid, Gliosis, Tau Phosphorylation, and Neuronal Loss

β-Amyloid1–42 Gene Transfer Model Exhibits Intraneuronal Amyloid, Gliosis, Tau Phosphorylation, and Neuronal Loss

Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin

Kinase activities increase during the development of tauopathy in htau mice

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