Kelleher RJ, Govindarajan A, Jung HY, Kang H, Tonegawa S.
Translational control by MAPK signaling in long-term synaptic plasticity and memory.
Cell. 2004 Feb 6;116(3):467-79.
PubMed.
ERK activation has been associated with the regulation of three major features of relevance to Alzheimer’s disease; these are hyperphosphorylation of tau (p-tau); memory and learning processes; and neurodegeneration. MEK1 is the upstream activator of ERK, and MEK inhibitors have been shown to prevent fibrillar Aβ-induced p-tau and neurodegeneration in hippocampal neurons (Rapoport and Ferreira, 2000). In postmortem brain tissue from Alzheimer’s disease patients, levels of phospho MEK1 have been demonstrated to be increased (Zhu et al., 2003), and furthermore, they were associated with pre-tangle neurons—a process that may precede Aβ deposition (Pei et al., 2002). These latter results are relevant to the study by Oddo et al. showing that LTP deficits occur before plaque and tangle pathology in a triple-transgenic model of Alzheimer’s disease (Oddo et al., 2003). However, the correlation between MEK1 and LTP has not been studied in in-vivo models for Alzheimer’s disease. Perhaps it would be possible, and certainly relevant, to extend the triple-transgenic mice model to a quadruple-transgenic, by further expressing a dominant negative MEK1? I leave the answer to specialists.
The merit of this study by Kelleher and colleagues is in the use of a model in which basal levels of active ERK are preserved. In this same study, the conditional inhibition of ERK leads to selective impairment of the phosphorylation of ribosomal protein S6, eIF4E, and 4EBP1, which play key roles in translational regulation necessary to LTP and long-term memory. The activity of eIF4E can be regulated by 4EBP1 and is influenced through many signaling pathways including PI3K and Ras, viral infections, and cellular stresses. It is noteworthy to mention two other factors—insulin and BDNF—suggested to be associated to Alzheimer’s disease; these also influence eIF4E. Insulin induces the phosphorylation of 4EBP1 and its dissociation from eIF4E (Gingras, 1999). Increasing evidence indicates that BDNF plays a key role in memory and learning. In addition, polymorphism in BDNF has been associated with Alzheimer’s disease (Riemenschneider et al., 2002). The cellular distribution of eIF4E is regulated by BDNF, a regulation that may involve integrins known to be involved in certain forms of synaptic plasticity (Smart et al., 2003).
In light of these results, further studies are needed to clarify the role of the MEK1 and the downstream translational regulators in learning and memory, and in the other neurodegenerative processes involved in Alzheimer’s disease.
References:
Rapoport M, Ferreira A.
PD98059 prevents neurite degeneration induced by fibrillar beta-amyloid in mature hippocampal neurons.
J Neurochem. 2000 Jan;74(1):125-33.
PubMed.
Zhu X, Sun Z, Lee HG, Siedlak SL, Perry G, Smith MA.
Distribution, levels, and activation of MEK1 in Alzheimer's disease.
J Neurochem. 2003 Jul;86(1):136-42.
PubMed.
Pei JJ, Braak H, An WL, Winblad B, Cowburn RF, Iqbal K, Grundke-Iqbal I.
Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease.
Brain Res Mol Brain Res. 2002 Dec 30;109(1-2):45-55.
PubMed.
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM.
Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.
Neuron. 2003 Jul 31;39(3):409-21.
PubMed.
Gingras AC, Raught B, Sonenberg N.
eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation.
Annu Rev Biochem. 1999;68:913-63.
PubMed.
Riemenschneider M, Schwarz S, Wagenpfeil S, Diehl J, Müller U, Förstl H, Kurz A.
A polymorphism of the brain-derived neurotrophic factor (BDNF) is associated with Alzheimer's disease in patients lacking the Apolipoprotein E epsilon4 allele.
Mol Psychiatry. 2002;7(7):782-5.
PubMed.
Smart FM, Edelman GM, Vanderklish PW.
BDNF induces translocation of initiation factor 4E to mRNA granules: evidence for a role of synaptic microfilaments and integrins.
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14403-8.
PubMed.
Comments
University of North Dakota
ERK activation has been associated with the regulation of three major features of relevance to Alzheimer’s disease; these are hyperphosphorylation of tau (p-tau); memory and learning processes; and neurodegeneration. MEK1 is the upstream activator of ERK, and MEK inhibitors have been shown to prevent fibrillar Aβ-induced p-tau and neurodegeneration in hippocampal neurons (Rapoport and Ferreira, 2000). In postmortem brain tissue from Alzheimer’s disease patients, levels of phospho MEK1 have been demonstrated to be increased (Zhu et al., 2003), and furthermore, they were associated with pre-tangle neurons—a process that may precede Aβ deposition (Pei et al., 2002). These latter results are relevant to the study by Oddo et al. showing that LTP deficits occur before plaque and tangle pathology in a triple-transgenic model of Alzheimer’s disease (Oddo et al., 2003). However, the correlation between MEK1 and LTP has not been studied in in-vivo models for Alzheimer’s disease. Perhaps it would be possible, and certainly relevant, to extend the triple-transgenic mice model to a quadruple-transgenic, by further expressing a dominant negative MEK1? I leave the answer to specialists.
The merit of this study by Kelleher and colleagues is in the use of a model in which basal levels of active ERK are preserved. In this same study, the conditional inhibition of ERK leads to selective impairment of the phosphorylation of ribosomal protein S6, eIF4E, and 4EBP1, which play key roles in translational regulation necessary to LTP and long-term memory. The activity of eIF4E can be regulated by 4EBP1 and is influenced through many signaling pathways including PI3K and Ras, viral infections, and cellular stresses. It is noteworthy to mention two other factors—insulin and BDNF—suggested to be associated to Alzheimer’s disease; these also influence eIF4E. Insulin induces the phosphorylation of 4EBP1 and its dissociation from eIF4E (Gingras, 1999). Increasing evidence indicates that BDNF plays a key role in memory and learning. In addition, polymorphism in BDNF has been associated with Alzheimer’s disease (Riemenschneider et al., 2002). The cellular distribution of eIF4E is regulated by BDNF, a regulation that may involve integrins known to be involved in certain forms of synaptic plasticity (Smart et al., 2003).
In light of these results, further studies are needed to clarify the role of the MEK1 and the downstream translational regulators in learning and memory, and in the other neurodegenerative processes involved in Alzheimer’s disease.
References:
Rapoport M, Ferreira A. PD98059 prevents neurite degeneration induced by fibrillar beta-amyloid in mature hippocampal neurons. J Neurochem. 2000 Jan;74(1):125-33. PubMed.
Zhu X, Sun Z, Lee HG, Siedlak SL, Perry G, Smith MA. Distribution, levels, and activation of MEK1 in Alzheimer's disease. J Neurochem. 2003 Jul;86(1):136-42. PubMed.
Pei JJ, Braak H, An WL, Winblad B, Cowburn RF, Iqbal K, Grundke-Iqbal I. Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease. Brain Res Mol Brain Res. 2002 Dec 30;109(1-2):45-55. PubMed.
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.
Gingras AC, Raught B, Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem. 1999;68:913-63. PubMed.
Riemenschneider M, Schwarz S, Wagenpfeil S, Diehl J, Müller U, Förstl H, Kurz A. A polymorphism of the brain-derived neurotrophic factor (BDNF) is associated with Alzheimer's disease in patients lacking the Apolipoprotein E epsilon4 allele. Mol Psychiatry. 2002;7(7):782-5. PubMed.
Smart FM, Edelman GM, Vanderklish PW. BDNF induces translocation of initiation factor 4E to mRNA granules: evidence for a role of synaptic microfilaments and integrins. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14403-8. PubMed.
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