Kuhn PH, Marjaux E, Imhof A, De Strooper B, Haass C, Lichtenthaler SF.
Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase.
J Biol Chem. 2007 Apr 20;282(16):11982-95.
PubMed.
Steve Barger University of Arkansas for Medical Sciences
Posted:
Kuhn et al. have produced a convincing body of work indicating that the type 2 receptor for IL-1 (IL-1R2) is processed by most of the same proteases that cleave the amyloid precursor protein.
At first glance, the relevance of these events for Alzheimer disease is questionable. The only clear connection of PS1 to AD is the FAD mutations that merely alter the site of APP cleavage without dramatically affecting the total γ-secretase processing of APP. In fact, Wiley et al. (1) demonstrated that FAD mutations in either APP or PS1 actually decrease the total γ-secretase cleavage of APP, and several investigators have suggested that the important parameter influenced by PS1 mutations is the ratio of cleavage at the 40 versus 42 amino acid of C99. To wit, these mutations seem to be silent with respect to most other γ-secretase substrates. In addition, the only clear aberrations in APP processing by α- and β-secretases are dependent upon mutations in APP itself, not in the proteases. Together, these points suggest that α-, β-, and γ-secretase activities in AD are normal with respect to every substrate save one: APP.
However, when viewed in the larger context of other substrates for APP-processing enzymes (e.g., TNF, CD44, and CD16), the addition of IL-1R2 to this group may indicate a coordination of immune/inflammatory molecules. Indeed, we and others have shown a proinflammatory role for secreted forms of APP (2-5). Thus, changes in secretase activity (as suggested by BACE elevation in early- to mid-stage AD) may influence inflammatory sequelae as much as do specific stimuli such as Aβ.
Still, the significance of IL-1R2 shedding is difficult to ascertain. Kuhn et al. favor the interpretation that release facilitates the decoy-style inhibition of IL-1 bioactivity. However, it might be argued that the concentration of IL-1R2 at the surface of any given cell is a better protection for that cell against ligation and activation of the type 1 receptor, especially when one considers that type 2 receptors are often expressed at levels several-fold higher than type 1. In fact, Re et al. (6) presented empirical data suggesting that surface expression of IL-1R2 was more effective than soluble receptor. One might even imagine that surface expression of IL-1R2 is used by IL-1-expressing cells to evoke a paracrine response in their neighbors without subjecting themselves to autocrine stimulation. Thus, the biological effect of type 2 receptor shedding may be a very complicated and nuanced shift in the distribution of the autocrine/paracrine balance of IL-1 activity for a tissue.
Kuhn et al. have thus presented a provocative dataset that produces the fuel that drives science forward: additional questions.
References:
Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M.
Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment.
J Neurochem. 2005 Sep;94(5):1189-201.
PubMed.
Barger SW, Harmon AD.
Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E.
Nature. 1997 Aug 28;388(6645):878-81.
PubMed.
Li Y, Liu L, Kang J, Sheng JG, Barger SW, Mrak RE, Griffin WS.
Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression.
J Neurosci. 2000 Jan 1;20(1):149-55.
PubMed.
Ikezu T, Luo X, Weber GA, Zhao J, McCabe L, Buescher JL, Ghorpade A, Zheng J, Xiong H.
Amyloid precursor protein-processing products affect mononuclear phagocyte activation: pathways for sAPP- and Abeta-mediated neurotoxicity.
J Neurochem. 2003 May;85(4):925-34.
PubMed.
Belmadani A, Tran PB, Ren D, Miller RJ.
Chemokines regulate the migration of neural progenitors to sites of neuroinflammation.
J Neurosci. 2006 Mar 22;26(12):3182-91.
PubMed.
Re F, Sironi M, Muzio M, Matteucci C, Introna M, Orlando S, Penton-Rol G, Dower SK, Sims JE, Colotta F, Mantovani A.
Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: a surface "receptor" with anti-interleukin-1 function.
J Exp Med. 1996 Apr 1;183(4):1841-50.
PubMed.
Comments
University of Arkansas for Medical Sciences
Kuhn et al. have produced a convincing body of work indicating that the type 2 receptor for IL-1 (IL-1R2) is processed by most of the same proteases that cleave the amyloid precursor protein.
At first glance, the relevance of these events for Alzheimer disease is questionable. The only clear connection of PS1 to AD is the FAD mutations that merely alter the site of APP cleavage without dramatically affecting the total γ-secretase processing of APP. In fact, Wiley et al. (1) demonstrated that FAD mutations in either APP or PS1 actually decrease the total γ-secretase cleavage of APP, and several investigators have suggested that the important parameter influenced by PS1 mutations is the ratio of cleavage at the 40 versus 42 amino acid of C99. To wit, these mutations seem to be silent with respect to most other γ-secretase substrates. In addition, the only clear aberrations in APP processing by α- and β-secretases are dependent upon mutations in APP itself, not in the proteases. Together, these points suggest that α-, β-, and γ-secretase activities in AD are normal with respect to every substrate save one: APP.
However, when viewed in the larger context of other substrates for APP-processing enzymes (e.g., TNF, CD44, and CD16), the addition of IL-1R2 to this group may indicate a coordination of immune/inflammatory molecules. Indeed, we and others have shown a proinflammatory role for secreted forms of APP (2-5). Thus, changes in secretase activity (as suggested by BACE elevation in early- to mid-stage AD) may influence inflammatory sequelae as much as do specific stimuli such as Aβ.
Still, the significance of IL-1R2 shedding is difficult to ascertain. Kuhn et al. favor the interpretation that release facilitates the decoy-style inhibition of IL-1 bioactivity. However, it might be argued that the concentration of IL-1R2 at the surface of any given cell is a better protection for that cell against ligation and activation of the type 1 receptor, especially when one considers that type 2 receptors are often expressed at levels several-fold higher than type 1. In fact, Re et al. (6) presented empirical data suggesting that surface expression of IL-1R2 was more effective than soluble receptor. One might even imagine that surface expression of IL-1R2 is used by IL-1-expressing cells to evoke a paracrine response in their neighbors without subjecting themselves to autocrine stimulation. Thus, the biological effect of type 2 receptor shedding may be a very complicated and nuanced shift in the distribution of the autocrine/paracrine balance of IL-1 activity for a tissue.
Kuhn et al. have thus presented a provocative dataset that produces the fuel that drives science forward: additional questions.
References:
Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M. Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment. J Neurochem. 2005 Sep;94(5):1189-201. PubMed.
Barger SW, Harmon AD. Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature. 1997 Aug 28;388(6645):878-81. PubMed.
Li Y, Liu L, Kang J, Sheng JG, Barger SW, Mrak RE, Griffin WS. Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression. J Neurosci. 2000 Jan 1;20(1):149-55. PubMed.
Ikezu T, Luo X, Weber GA, Zhao J, McCabe L, Buescher JL, Ghorpade A, Zheng J, Xiong H. Amyloid precursor protein-processing products affect mononuclear phagocyte activation: pathways for sAPP- and Abeta-mediated neurotoxicity. J Neurochem. 2003 May;85(4):925-34. PubMed.
Belmadani A, Tran PB, Ren D, Miller RJ. Chemokines regulate the migration of neural progenitors to sites of neuroinflammation. J Neurosci. 2006 Mar 22;26(12):3182-91. PubMed.
Re F, Sironi M, Muzio M, Matteucci C, Introna M, Orlando S, Penton-Rol G, Dower SK, Sims JE, Colotta F, Mantovani A. Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: a surface "receptor" with anti-interleukin-1 function. J Exp Med. 1996 Apr 1;183(4):1841-50. PubMed.
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