This is a very thorough study that provides the Hq mutant mouse as the "first in vivo model for studying the role of oxidative stress on aberrant cell cycle re-entry and subsequent apoptosis." Thus, it links two classes of phenomena that have been described in the AD brain. In addition, the authors describe a selective effect on death of neurons in the cerebellum and retina. They convincingly demonstrate that other sets of neurons are resistant to the cell death they demonstrate in cerebellum and retina. The authors comment that "Similar to many gene products involved in neurodegenerative and other disorders, the expression pattern of AIF (the gene affected in their mutant) is much wider than the tissues phenotypically affected." They suggest that unaffected sets of neurons may be resistant to cell death by virtue of parallel mechanisms for coping with, in this case, peroxide production. This is a concept that has broad applicability beyond the class of challenge referred to here. It is notable that authors do not find differential selectivity to cell death in the mutant mice...  Read more

This is a very thorough study that provides the Hq mutant mouse as the "first in vivo model for studying the role of oxidative stress on aberrant cell cycle re-entry and subsequent apoptosis." Thus, it links two classes of phenomena that have been described in the AD brain. In addition, the authors describe a selective effect on death of neurons in the cerebellum and retina. They convincingly demonstrate that other sets of neurons are resistant to the cell death they demonstrate in cerebellum and retina. The authors comment that "Similar to many gene products involved in neurodegenerative and other disorders, the expression pattern of AIF (the gene affected in their mutant) is much wider than the tissues phenotypically affected." They suggest that unaffected sets of neurons may be resistant to cell death by virtue of parallel mechanisms for coping with, in this case, peroxide production. This is a concept that has broad applicability beyond the class of challenge referred to here. It is notable that authors do not find differential selectivity to cell death in the mutant mice when other challenges are presented, including serum starvation.

In this paper both terms "cell cycle" and "apoptosis" are variously used. Certainly the two are related in ways that are not yet completely defined. However, certain specific commonalities are known. For example cyclin B and CDK 1 are required for cell death as well as being important components of the cell cycle. (See Bob Freeman "The cell cycle and neuronal cell death" in Cell Death and Diseases of the Nervous System, V. Koliatsos and R Ratan eds, Humana Press, 1999, for a review of the relation between the cell cycle and apototic cell death.)

As is true of a nice paper, there are many issues raised. Limiting to those that relate to AD, how important is it that the selectivity found in the Hq mutant mice is restricted to cells that are traditionally unaffected in AD? Is the expression of cell cycle and cell death seen in AD through the same mechanism suggested in the Hq mutant? It is probable that other challenges, such as growth factor changes, that do not demonstrably affect the Hq mutants, play a significant role in AD. Although much attention has been recently devoted to the C terminal fragment of APP in AD, this paper suggests another class of mechanism whose potential applicability to AD requires experimental exploration.

View all comments by Paul Coleman

I loved this paper.This work makes a compelling case for the involvement of oxidative stress in unscheduled cell cycle re-entry of postmitotic neurons, with consequent apoptosis. What is remarkable is the selective vulnerability of cerebellar and retinal neurons, despite of the fact that the AIF gene, in which the ecotropic provirus inserted, is expressed throughout brain. The Hq mutant mouse might therefore serve as a model not only for studying how oxidative damage leads to activation of the cell cycle in cerebellar neurons, but also for delineating the basis of the resistance to this death scheme of hippocampal and cerebral neurons for example. It is also curious that only neurons of the CNS seem to be affected in the Hq mouse – or was this the only tissue studied here? I did a search for more comprehensive phenotypic description of the Hq mouse, but found only one report about ichthyosis, a condition in which the skin becomes thickened, devoid of hair, and scaly. AIF is, apparently, expressed ubiquitously in normal tissues and in a variety of cancer cell lines. This Hq...  Read more

I loved this paper.This work makes a compelling case for the involvement of oxidative stress in unscheduled cell cycle re-entry of postmitotic neurons, with consequent apoptosis. What is remarkable is the selective vulnerability of cerebellar and retinal neurons, despite of the fact that the AIF gene, in which the ecotropic provirus inserted, is expressed throughout brain. The Hq mutant mouse might therefore serve as a model not only for studying how oxidative damage leads to activation of the cell cycle in cerebellar neurons, but also for delineating the basis of the resistance to this death scheme of hippocampal and cerebral neurons for example. It is also curious that only neurons of the CNS seem to be affected in the Hq mouse – or was this the only tissue studied here? I did a search for more comprehensive phenotypic description of the Hq mouse, but found only one report about ichthyosis, a condition in which the skin becomes thickened, devoid of hair, and scaly. AIF is, apparently, expressed ubiquitously in normal tissues and in a variety of cancer cell lines. This Hq mouse model would also be useful for determining why mutation of the AIF gene affects only certain tissue types.

View all comments by Inez Vincent

Harlequin and Alzheimer Disease: Remarkable Parallels
If it takes years to die, it is not by an apoptotic mechanism. Klein and colleagues (2002) present an excellent model for this assertion and a couple of other phenomena that are present in Alzheimer disease (AD) and other neurodegenerative conditions. First, it shows how apoptotic death can be avoided in neurons that really do need to stick around (Raina et al., 2001). This phenomenon is remarkably similar to one we previously termed "abortosis" (Raina et al., 2001). Additionally, it provides a mechanism for how oxidative stress is proximal in the pathophysiology of AD (Nunomura et al., 2001) and by itself can lead to cell cycle re-entry in vulnerable neurons with subsequent arrest of the cell cycle program. Indeed, the combination of oxidative stress and cell cycle re-entry, in a "two-hit" manner, may be what bring forth the mature neurodegenerative phenotype in AD (Zhu et al., 2001). It will be exciting to see to what extent the Harlequin mutant mouse model parallels other aspects of neurodegenerative...  Read more

Harlequin and Alzheimer Disease: Remarkable Parallels
If it takes years to die, it is not by an apoptotic mechanism. Klein and colleagues (2002) present an excellent model for this assertion and a couple of other phenomena that are present in Alzheimer disease (AD) and other neurodegenerative conditions. First, it shows how apoptotic death can be avoided in neurons that really do need to stick around (Raina et al., 2001). This phenomenon is remarkably similar to one we previously termed "abortosis" (Raina et al., 2001). Additionally, it provides a mechanism for how oxidative stress is proximal in the pathophysiology of AD (Nunomura et al., 2001) and by itself can lead to cell cycle re-entry in vulnerable neurons with subsequent arrest of the cell cycle program. Indeed, the combination of oxidative stress and cell cycle re-entry, in a "two-hit" manner, may be what bring forth the mature neurodegenerative phenotype in AD (Zhu et al., 2001). It will be exciting to see to what extent the Harlequin mutant mouse model parallels other aspects of neurodegenerative diseases.

Arun K. Raina, George Perry, Xiongwei Zhu, and Mark A. Smith. Institute of Pathology, Case Western Reserve University, Cleveland, Ohio USA; mas21@po.cwru.edu

References
Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL. The harlequin mouse mutation down-regulates apoptosis-inducing factor. Nature 419:367-374, 2002.

Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759-767, 2001. Abstract

Raina AK, Hochman A, Zhu X, Rottkamp CA, Nunomura A, Siedlak SL, Boux H, Castellani RJ, Perry G, Smith MA. Abortive apoptosis in Alzheimer’s disease. Acta Neuropathol 101:305-310, 2001. Abstract

Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA. Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the "two hit" hypothesis. Mech Ageing Dev 123:39-46, 2001. Abstract

View all comments by George Perry