p38 Mitogen Activated Protein Kinase as a Therapeutic Target for Alzheimer's Disease

2002 ◽  
Vol 19 (3) ◽  
pp. 295-300 ◽  
Author(s):  
Stacie A. Dalrymple
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Therapeutic Target ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

scholarly journals Increased tau Phosphorylation on Mitogen-Activated Protein Kinase Consensus Sites and Cognitive Decline in Transgenic Models for Alzheimer's Disease and FTDP-17: Evidence for Distinct Molecular Processes Underlying tau Abnormalities

2005 ◽  
Vol 25 (1) ◽  
pp. 278-293 ◽  
Author(s):  
Sarah L. Lambourne ◽  
Lynda A. Sellers ◽  
Toby G. Bush ◽  
Shewly K. Choudhury ◽  
Piers C. Emson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Tau Phosphorylation ◽  
Mitogen Activated Protein Kinase ◽  
Chromosome 17 ◽  
Mapk Activation ◽  
Age Dependent ◽  
Mitogen Activated Protein ◽  
Activation Status

ABSTRACT Abnormal tau phosphorylation occurs in several neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here, we compare mechanisms of tau phosphorylation in mouse models of FTDP-17 and AD. Mice expressing a mutated form of human tau associated with FTDP-17 (tauV337M) showed age-related increases in exogenous tau phosphorylation in the absence of increased activation status of a number of kinases known to phosphorylate tau in vitro. In a “combined” model, expressing both tauV337M and the familial amyloid precursor protein AD mutation APPV717I in a CT100 fragment, age-dependent tau phosphorylation occurred at the same sites and was significantly augmented compared to “single” tauV337M mice. These effects were concomitant with increased activation status of mitogen-activated protein kinase (MAPK) family members (extracellular regulated kinases 1 and 2, p38, and c-Jun NH2-terminal kinase) but not glycogen synthase kinase-3αβ or cyclin-dependent kinase 5. The increase in MAPK activation was a discrete effect of APPV717I-CT100 transgene expression as near identical changes were observed in single APPV717I-CT100 mice. Age-dependent deficits in memory were also associated with tauV337M and APPV717I-CT100 expression. The data reveal distinct routes to abnormal tau phosphorylation in models of AD and FTDP-17 and suggest that in AD, tau irregularities may be linked to processing of APP C-terminal fragments via specific effects on MAPK activation status.

scholarly journals p63α and γ Induce TAU Phosphorylation in Cultured Mammalian Cells

2010 ◽  
Vol 4 ◽  
pp. JEN.S6295
Author(s):  
Claudie Hooper ◽  
Reem Soliman ◽  
Simon Lovestone ◽  
Richard Killick
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Mammalian Cells ◽  
Neuronal Development ◽  
Glycogen Synthase ◽  
Tau Phosphorylation ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Here we show by western blotting that transcriptionally active isoforms of p63 (p63α and p63γ) induce the phosphorylation of human 2N4R tau at the tau-1/AT8 epitope in HEK293a cells; a phospho-epitope increased in Alzheimer's disease. Confocal microscopy shows that tau and p63α are spatially separated intracellularly. Tau was found in the cytoskeletal compartment, whilst p63α was located in the nucleus, indicating that the effects of p63 on tau phosphorylation are indirectly mediated. Tau phosphorylation occurred independently of the known tau kinases, protein kinase C delta (PKCδ), c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), glycogen synthase kinase 3 (GSK3), v-akt murine thymoma viral oncogene homolog (AKT) and cyclin-dependent kinase 5 (Cdk5) and the tau protein phosphatases (PP), PP1 and PP2A-Aα/β. Considering that p63 and tau are both associated with developmental processes, these findings have ramifications for neuronal development and synaptic plasticity and also neurodegenerative diseases such as Alzheimer's disease and other tauopathies.

The Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s Disease

Neurosignals ◽  
2002 ◽  
Vol 11 (5) ◽  
pp. 270-281 ◽  
Author(s):  
Xiongwei Zhu ◽  
Hyoung-gon Lee ◽  
Arun K. Raina ◽  
George Perry ◽  
Mark A. Smith
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

scholarly journals The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer’s Disease

2021 ◽  
Vol 22 (6) ◽  
pp. 3136
Author(s):  
Jacques Hugon ◽  
Claire Paquet
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
P38 Map Kinase ◽  
Translation Initiation Factor ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Mitogen Activated Protein

Neuropathological lesions in Alzheimer’s disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aβ accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.

Localization of the mitogen activated protein kinase ERK2 in Alzheimer's disease neurofibrillary tangles and senile plaque neurites

1993 ◽  
Vol 618 (2) ◽  
pp. 333-337 ◽  
Author(s):  
John Q. Trojanowski ◽  
Madhumalti Mawal-Dewan ◽  
M. Luise Schmidt ◽  
John Martin ◽  
Virginia M.-Y. Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Neurofibrillary Tangles ◽  
Senile Plaque ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein
Sign in / Sign up

Export Citation Format

Share Document