Kriem B, Sponne I, Fifre A, Malaplate-Armand C, Lozac'h-Pillot K, Koziel V, Yen-Potin FT, Bihain B, Oster T, Olivier JL, Pillot T. Cytosolic phospholipase A2 mediates neuronal apoptosis induced by soluble oligomers of the amyloid-beta peptide. FASEB J. 2005 Jan;19(1):85-7. PubMed.
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Kriem and colleagues report that soluble oligomeric forms of amyloid peptide induce cytoplasmic PLA2 with subsequent neuronal apoptosis, which is reduced by inhibitors of p38.
It's of interest that c-Abl is an activator of p38 MAP kinase (1).
Might we suspect that Gleevec may also reduce p38 MAP kinase activity as a result of Aβ overexpression?
P38 MAP kinase is activated in the early stages of AD (2).
The reports that minocycline is able to inhibit NO-induced phosphorylation of p38 MAP kinase in rat cerebellar granule neurons (3) and prevent nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson disease would suggest that this treatment may be beneficial in AD (4). MPTP is an activator of cytoplasmic PLA2 and many of the problems may be explained by the subsequent lysophosphatidylcholine cytotoxicity.
PLIP and Tip60 coimmunoprecipitate and colocalize with cPLA2 within the nuclei (5).
The cytoplasmic tail of APP forms a multimeric complex with the nuclear adaptor protein Fe65 and the histone acetyltransferase Tip60 (6).
Interesting that p38 is increased in AD and DS, yet not in schizophrenia (7).
Minocycline prevents cholinergic loss in a mouse model of Down syndrome (8).
I'd be interested to hear whether p38 activity is reduced in the Ashley Bush chloroquine group, as Bossy-Wetzel et al. (9) report that free Zn2+ causes p38 MAP kinase activation.
References:
Sanchez-Prieto R, Sanchez-Arevalo VJ, Servitja JM, Gutkind JS. Regulation of p73 by c-Abl through the p38 MAP kinase pathway. Oncogene. 2002 Jan 31;21(6):974-9. PubMed.
Sun A, Liu M, Nguyen XV, Bing G. P38 MAP kinase is activated at early stages in Alzheimer's disease brain. Exp Neurol. 2003 Oct;183(2):394-405. PubMed.
Lin S, Zhang Y, Dodel R, Farlow MR, Paul SM, Du Y. Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons. Neurosci Lett. 2001 Nov 23;315(1-2):61-4. PubMed.
Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14669-74. PubMed.
Sheridan AM, Force T, Yoon HJ, O'Leary E, Choukroun G, Taheri MR, Bonventre JV. PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production. Mol Cell Biol. 2001 Jul;21(14):4470-81. PubMed.
Cao X, Südhof TC. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001 Jul 6;293(5527):115-20. PubMed.
Swatton JE, Sellers LA, Faull RL, Holland A, Iritani S, Bahn S. Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain. Eur J Neurosci. 2004 May;19(10):2711-9. PubMed.
Hunter CL, Bachman D, Granholm AC. Minocycline prevents cholinergic loss in a mouse model of Down's syndrome. Ann Neurol. 2004 Nov;56(5):675-88. PubMed.
Bossy-Wetzel E, Talantova MV, Lee WD, Schölzke MN, Harrop A, Mathews E, Götz T, Han J, Ellisman MH, Perkins GA, Lipton SA. Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron. 2004 Feb 5;41(3):351-65. PubMed.
University of Concepcion
I read the paper and enjoyed the new view presented by these authors.... However, I do not understand the definition of "soluble oligomer." Is this a protofibrillar solution? Are amylospheroids in the sample? Or is there just monomer in the solution? It is a good idea to check this point, because we need to separate the "normal" effects of amyloid-β and the "toxic" effect of the aggregated form of this peptide.
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