This paper by Lei et al. provides two important novel observations. Firstly, as a parkinsonian model, the tau knockout mice are exciting because they do not show symptoms of disease until 12 months of age; thus, similar to Parkinson’s patients, there is an age dependency for symptom onset and presumably host vulnerability. Secondly, the data demonstrate that tau itself is not the culprit but an age-dependent accumulation of iron because tau has been absent from birth in the mice but symptom onset is not until iron levels reach a threshold level. Therefore, the role of iron in the pathogenesis of Parkinson's becomes even stronger. Moreover, the data continue to implicate amyloid-β precursor protein (APP) in the neuronal regulation of iron; although one can wonder why, given the reported importance of APP as a neuronal exporter of iron, it would take 12 months for enough iron to accumulate to see an effect. It would be informative to know the expression of ferritin in the neurons. Ferritin could offer protection from the iron by sequestering it. A number of years ago we had argued...  Read more

This paper by Lei et al. provides two important novel observations. Firstly, as a parkinsonian model, the tau knockout mice are exciting because they do not show symptoms of disease until 12 months of age; thus, similar to Parkinson’s patients, there is an age dependency for symptom onset and presumably host vulnerability. Secondly, the data demonstrate that tau itself is not the culprit but an age-dependent accumulation of iron because tau has been absent from birth in the mice but symptom onset is not until iron levels reach a threshold level. Therefore, the role of iron in the pathogenesis of Parkinson's becomes even stronger. Moreover, the data continue to implicate amyloid-β precursor protein (APP) in the neuronal regulation of iron; although one can wonder why, given the reported importance of APP as a neuronal exporter of iron, it would take 12 months for enough iron to accumulate to see an effect. It would be informative to know the expression of ferritin in the neurons. Ferritin could offer protection from the iron by sequestering it. A number of years ago we had argued that it is not iron that is problematic for cells, but the mismanagement of iron, including in Parkinson’s brains (Connor et al., 1995). The accumulation of ferritin could be expected to have limited impact in acute models of tyrosine hydroxylase neuronal degeneration in response to toxin injections, but in a chronic model, as in the tau knockout mice of Lei et al., a failure of ferritin expression and protection could provide insights into how iron accumulation is problematic. Loss of ferritin may also explain why the cells do not respond better to the iron accumulation by protecting themselves and provide potential targets for therapy. If ferritin could be induced, would it be protective in this model? It was shown that expression of ferritin in tyrosine hydroxylase neurons protects them from MPTP (Kaur et al., 2003). Maybe the cells do express ferritin, but over time the amounts of ferritin become insufficient to offer protection.

The tau knockout animal model could also be valuable in providing MRI data that could help answer when, in the time frame of symptom onset, iron accumulation in the SN begins. This is important, since the clioquinol was given beginning at 6.5 months for five months. It is remarkable that over the length of time this drug was present, there was no loss of liver iron, or that neither copper nor zinc levels were affected by this drug.

This study joins a number of others on various degenerative diseases or models such as stroke, ALS, and multiple sclerosis in demonstrating that providing an iron chelator prior to the onset of damage or disease was protective. Thus, there is a long line of evidence that limiting iron is beneficial. The challenge ahead is to determine if the iron reverses or rescues symptoms similar to the single dose of L-DOPA. For now, we have a new, exciting animal model that continues to support the findings that APP has important ferroxidase activity in the brain, and that mutations in proteins as important as tau require additional factors, such as iron accumulation, to induce neurodegeneration. The data also strongly argue that iron is pathogenic in PD and not a bystander effect secondary to neurodegeneration.

References:
Connor JR, Snyder BS, Arosio P, Loeffler DA, Lewitt P. A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer's diseased brains. J Neurochem. 1995 Aug;65(2):717-24. Abstract

Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, Viswanath V, Jacobs R, Yang L, Beal MF, Dimonte D, Volitaskis I, Ellerby L, Cherny RA, Bush AI, Andersen JK. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron. 2003 Mar 27;37(6):899-909. Abstract

View all comments by James R. Connor

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 Samuel Gandy

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...  Read more

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. Abstract

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. Abstract

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. Abstract

View all comments by Jack T. Rogers