Zhang H, Zhang YW, Chen Y, Huang X, Zhou F, Wang W, Xian B, Zhang X, Masliah E, Chen Q, Han JD, Bu G, Reed JC, Liao FF, Chen YG, Xu H. Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration. J Neurosci. 2012 Oct 31;32(44):15565-76. PubMed.

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  1. There has been a longstanding curiosity in the field of Alzheimer's research regarding possible relationships between APP/Aβ and the process of apoptosis. Aβ oligomer toxicity is closely associated with neurotoxicity, but typical programmed cell death (aka apoptosis) has not been robustly indicated. Caspase cleavage of APP and PS2 have long stood as possible nexuses whereby APP metabolism and apoptosis might converge. Now Xu and colleagues discover a new protein, dubbed appoptosin, that bridges the gap between APP and mitochondrial physiology and apoptosis. Appoptosin levels are increased in AD brain and infarcted brain, and levels of any protein that buck the trend and rise during neuronal death are usually worth noting. Downregulation of appoptosin protects neurons from Aβ toxicity and glutamate toxicity, raising the possibility that therapeutic reduction of brain appoptosin becomes the latest novel strategy for protecting the brain besieged by AD.

    View all comments by Sam Gandy

  2. Zhang et al. have identified further links between Alzheimer's disease and iron metabolism via their discovery of a role for appoptosin, which they reported to be a novel amyloid precursor protein (APP)-binding protein after yeast hybrid analysis.

    Han Zhang's team collaborated with Huaxi Xu's team to conclusively show that appoptosin expression causes mitochondrial-driven apoptosis. However, more significantly, it can bind the C-terminal of the APP, tethered to the membrane. After damage, or even secretase cleavage, appoptosin moves to the mitochondria and is proposed to have a significant role in mitochondrial heme biosynthesis. Excess heme is known to generate reactive oxygen species by Fenton chemistry and thus cause neuronal death, as after hemorrhage, for example.

    Intriguing links to iron metabolism yet again arise from this tour de force since the findings are consistent with the 2010 demonstration that APP also binds ferroportin and is considered an iron export ferroxidase via its N-terminus (see Duce et al., 2010).

    Clearly, the APP/appoptosin partnership has a significant role in iron homeostasis.

    This is particularly evident by the RNA binding protein iron-regulatory protein 1 (IRP1), which controls the rate of iron/heme-dependent translation of APP to thereby efflux excess iron from neural cells at risk from heme or iron overload (Cho et al., 2010).

    The link between APP and heme/iron metabolism, and now apoptosis, is supported by more evidence that, like APP, appoptosin has a central role in iron homeostasis, and that mistakes in this homeostasis can kill neurons.

    Indeed, genetic mutations to the appoptosin gene cause recessive congenital sideroblastic anemia (Guernsey et al., 2009, a reference in this paper).

    References:

    Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell. 2010 Sep 17;142(6):857-67. PubMed.

    Cho HH, Cahill CM, Vanderburg CR, Scherzer CR, Wang B, Huang X, Rogers JT. Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1. J Biol Chem. 2010 Oct 8;285(41):31217-32. PubMed.

    Guernsey DL, Jiang H, Campagna DR, Evans SC, Ferguson M, Kellogg MD, Lachance M, Matsuoka M, Nightingale M, Rideout A, Saint-Amant L, Schmidt PJ, Orr A, Bottomley SS, Fleming MD, Ludman M, Dyack S, Fernandez CV, Samuels ME. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat Genet. 2009 Jun;41(6):651-3. PubMed.

    View all comments by Jack T. Rogers

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