cAMP-Dependent Protein Kinase Phosphorylations on Tau in Alzheimer’s Disease

Jicha, Gregory A.; Weaver, Charles L.; Lane, Eric; Vianna, Cintia; Kress, Yvonne; Rockwood, Julia M.; Davies, Peter

doi:10.1523/jneurosci.19-17-07486.1999

Cited by 191 publications

(167 citation statements)

References 47 publications

(56 reference statements)

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“…PG5 recognizes phosphorlyated tau at serine 409 and marks neurofibrillary pathology in early and advanced AD, but not in normal brain tissue (45). PG5 staining in our P301S brain sections resulted in cell body and neuropil signal in both the cortex and hippocampus, starting at ∼6 mo, and increased with age ( Fig.…”

Section: Comparison Of Seeding With Standard Histopathological Markersmentioning

confidence: 85%

Proteopathic tau seeding predicts tauopathy in vivo

Holmes

Furman

Mahan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

522

792

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Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼300 fM) and synuclein (∼300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.amyloid | neuropathology | dementia | aging P rotein aggregation characterizes many neurodegenerative disorders, including Alzheimer's disease (AD) and the related tauopathies. These disorders feature the accumulation of fibrillar deposits of the microtubule-associated protein tau with progressive deterioration of the central nervous system. Tau pathology and its associated brain atrophy do not appear randomly throughout the brain, but rather progress along distinct neural networks (1-5). This aspect suggests a role for transcellular spread of a pathogenic agent via neural connections. Our laboratory and others have previously hypothesized that tau aggregates-or seeds-serve as this agent of spread, transmitting the aggregated state from cell to cell via prion-like mechanisms (6-15).Mounting fundamental insights support this hypothesis. Tau seeds applied to the outside of cells bind the cell surface by attaching to heparan sulfate proteoglycans, triggering uptake by macropinocytosis (13). Upon internalization, tau seeds nucleate the fibrillization of endogenous tau monomer via templated conformational change, or seeding (8, 10). Tau seeding requires a critical unit of size for activity, as only particular species propagate the aggregated state (16). In vivo studies have described tau protein spreading from local sites to distant regions, presumably via transsynaptic movement (11,12,(17)(18)(19). Finally, our laboratory and another recently demonstrated that tau propagates discrete amyloid conformations through the brains of animals that give rise to unique neuropathologies (18,20).Despite this evidence, it remains unclear wheth...

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Section: Comparison Of Seeding With Standard Histopathological Markersmentioning

confidence: 85%

Proteopathic tau seeding predicts tauopathy in vivo

Holmes

Furman

Mahan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

522

792

View full text Add to dashboard Cite

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“…These data identify both PKA and GSK-3 as potential therapeutic targets for AD and other tauopathies that are characterized by neurofibrillary degeneration associated with the abnormal hyperphosphorylation of tau. It is interesting to note that 14-3-3 and ␣-synuclein, both of which stimulate PKA activity (61,62), are colocalized with neurofibrillary tangles in AD brain (63).…”

Section: Discussionmentioning

confidence: 99%

Tau Becomes a More Favorable Substrate for GSK-3 When It Is Prephosphorylated by PKA in Rat Brain

Liu

Zhang

et al. 2004

Journal of Biological Chemistry

176

117

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Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and other tauopathies and is believed to lead to neurodegeneration in this family of diseases. Here we show that infusion of forskolin, a specific cAMP-dependent protein kinase A (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by severalfold and concurrently enhanced the phosphorylation of tau at Ser-214, Ser-198, Ser-199, and or Ser-202 (Tau-1 site) and Ser-396 and or Ser-404 (PHF-1 site), which are among the major abnormally hyperphosphorylated sites seen in AD. PKA activation positively correlated to the extent of tau phosphorylation at these sites. Infusion of forskolin together with PKA inhibitor or glycogen synthase kinase-3 (GSK-3) inhibitor revealed that the phosphorylation of tau at Ser-214 was catalyzed by PKA and that the phosphorylation at both the Tau-1 and the PHF-1 sites is induced by basal level of GSK-3, because forskolin activated PKA and not GSK-3 and inhibition of the latter inhibited the phosphorylation at Tau-1 and PHF-1 sites. Inhibition of cdc2, cdk5, or MAPK had no significant effect on the forskolin-induced hyperphosphorylation of tau. Forskolin inhibited spatial memory in a dose-dependent manner in the absence but not in the presence of R p -adenosine 3 ,5 -cyclic monophosphorothioate triethyl ammonium salt, a PKA inhibitor. These results demonstrate for the first time that phosphorylation of tau by PKA primes it for phosphorylation by GSK-3 at the Tau-1 and the PHF-1 sites and that an associated loss in spatial memory is inhibited by inhibition of the hyperphosphorylation of tau. These data provide a novel mechanism of the hyperphosphorylation of tau and identify both PKA and GSK-3 as promising therapeutic targets for AD and other tauopathies.

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“…PKA is a non-proline-directed kinase and phosphorylates tau at several sites including Ser 214 but not at Ser 202 (34,41,42). To gain more evidence in favor of the idea that Ser 202 phosphorylation is the major factor in the tau mobility shift on SDS-PAGE, we phosphorylated tau WT and S202A by Cdk5 or PKA for 120 min.…”

Section: Effect Of Ftdp-17 Mutations On Tau Phosphorylation-as Shown mentioning

confidence: 99%

Familial FTDP-17 Missense Mutations Inhibit Microtubule Assembly-promoting Activity of Tau by Increasing Phosphorylation at Ser202 in Vitro

Han

Qureshi

et al. 2009

Journal of Biological Chemistry

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In Alzheimer disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and other tauopathies, tau accumulates and forms paired helical filaments (PHFs) in the brain. Tau isolated from PHFs is phosphorylated at a number of sites, migrates as ϳ60-, 64-, and 68-kDa bands on SDS-gel, and does not promote microtubule assembly. Upon dephosphorylation, the PHF-tau migrates as ϳ50 -60-kDa bands on SDS-gels in a manner similar to tau that is isolated from normal brain and promotes microtubule assembly. The site(s) that inhibits microtubule assembly-promoting activity when phosphorylated in the diseased brain is not known. In this study, when tau was phosphorylated by Cdk5 in vitro, its mobility shifted from ϳ60-kDa bands to ϳ64-and 68-kDa bands in a time-dependent manner. This mobility shift correlated with phosphorylation at Ser 202 , and Ser 202 phosphorylation inhibited tau microtubule-assembly promoting activity. When several tau point mutants were analyzed, G272V, P301L, V337M, and R406W mutations associated with FTDP-17, but not nonspecific mutations S214A and S262A, promoted Ser 202 phosphorylation and mobility shift to a ϳ68-kDa band. Furthermore, Ser 202 phosphorylation inhibited the microtubule assembly-promoting activity of FTDP-17 mutants more than of WT. Our data indicate that FTDP-17 missense mutations, by promoting phosphorylation at Ser 202 , inhibit the microtubule assembly-promoting activity of tau in vitro, suggesting that Ser 202 phosphorylation plays a major role in the development of NFT pathology in AD and related tauopathies. Neurofibrillary tangles (NFTs)4 and senile plaques are the two characteristic neuropathological lesions found in the brains of patients suffering from Alzheimer disease (AD).The major fibrous component of NFTs are paired helical filaments (PHFs) (for reviews see Refs. 1-3). Initially, PHFs were found to be composed of a protein component referred to as "A68" (4). Biochemical analysis reveled that A68 is identical to the microtubule-associated protein, tau (4, 5). Some characteristic features of tau isolated from PHFs (PHF-tau) are that it is abnormally hyperphosphorylated (phosphorylated on more sites than the normal brain tau), does not bind to microtubules, and does not promote microtubule assembly in vitro. Upon dephosphorylation, PHF-tau regains its ability to bind to and promote microtubule assembly (6, 7). Tau hyperphosphorylation is suggested to cause microtubule instability and PHF formation, leading to NFT pathology in the brain (1-3).PHF-tau is phosphorylated on at least 21 proline-directed and non-proline-directed sites (8, 9). The individual contribution of these sites in converting tau to PHFs is not entirely clear. However, some sites are only partially phosphorylated in PHFs (8), whereas phosphorylation on specific sites inhibits the microtubule assembly-promoting activity of tau (6, 10). These observations suggest that phosphorylation on a few sites may be responsible and sufficient for causing tau dysfunction in AD.Tau purified ...

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cAMP-Dependent Protein Kinase Phosphorylations on Tau in Alzheimer’s Disease

Cited by 191 publications

References 47 publications

Proteopathic tau seeding predicts tauopathy in vivo

Proteopathic tau seeding predicts tauopathy in vivo

Tau Becomes a More Favorable Substrate for GSK-3 When It Is Prephosphorylated by PKA in Rat Brain

Familial FTDP-17 Missense Mutations Inhibit Microtubule Assembly-promoting Activity of Tau by Increasing Phosphorylation at Ser202 in Vitro

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