This is a very interesting paper, which further supports a functional role for reactive oxygen species (ROS)-mediated oxidative stress in neurodegeneration and cognitive-function decline. Aging is the strongest risk factor to develop sporadic Alzheimer disease (AD), and age-related accumulation of oxidative stress end-products with subsequent cell damage provides a strong support for the so-called oxidative stress hypothesis of aging as well as AD. Oxidative stress is a biological condition where the amount of ROS formed exceeds the ability to keep them at physiological levels. In a very elegant way, Ohsawa et al. now show that if one important neutralizing enzyme, namely aldehyde dehydrogenase 2 (ALDH-2), is not working properly in the mouse central nervous system (CNS), the results are age-dependent memory impairment, further increase in lipid peroxidation, neurodegeneration, and a significant reduction in their lifespan.

Another interesting aspect of the study is that the authors demonstrate that all the described pathological features are accelerated in mice that are...  Read more

This is a very interesting paper, which further supports a functional role for reactive oxygen species (ROS)-mediated oxidative stress in neurodegeneration and cognitive-function decline. Aging is the strongest risk factor to develop sporadic Alzheimer disease (AD), and age-related accumulation of oxidative stress end-products with subsequent cell damage provides a strong support for the so-called oxidative stress hypothesis of aging as well as AD. Oxidative stress is a biological condition where the amount of ROS formed exceeds the ability to keep them at physiological levels. In a very elegant way, Ohsawa et al. now show that if one important neutralizing enzyme, namely aldehyde dehydrogenase 2 (ALDH-2), is not working properly in the mouse central nervous system (CNS), the results are age-dependent memory impairment, further increase in lipid peroxidation, neurodegeneration, and a significant reduction in their lifespan.

Another interesting aspect of the study is that the authors demonstrate that all the described pathological features are accelerated in mice that are genetically deficient for apolipoprotein E (ApoE). ApoE is a very important chaperon protein, which has been involved in cholesterol metabolism as well as in Aβ transport (1,2). Previous work showed that its genetic absence results in a dramatic increase in plasma cholesterol and vascular oxidative stress (3). We have shown that aged ApoE-deficient mice manifest clear signs of oxidative stress in their CNS, which can be rescued by the genetic absence of an important source of ROS, i.e., 12/15-lipoxygenase (4,5). Interestingly, early work by Masliah et al. showed that these mice also develop neurodegenerative alterations and cognitive impairments (6).

Thus, it is not surprising at all that the combination of ApoE deficiency with the dysfunction of ALDH-2 has a synergistic pathological effect in vivo. To what extent the current observation translates to the human scenario is not clear at this time. All of the data available point to the ApoE4 isoform as a genetic risk factor for late-onset AD (7); therefore, it would have been very interesting to see whether or not this synergism exists between human ApoE4 allele and ALDH-2 variant used in the present study. My guess is that the same group is probably working on this already.

References:
1. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622-30. Abstract

2. Wisniewski T, Golabek A, Matsubara E, Ghiso J, Frangione B. Apolipoprotein E: binding to soluble Alzheimer's beta-amyloid. Biochem Biophys Res Commun. 1993 Apr 30;192(2):359-65. Abstract

3. Praticò D, Tangirala RK, Hörkkö S, Witztum JL, Palinski W, FitzGerald GA. Circulating autoantibodies to oxidized cardiolipin correlate with isoprostane F(2alpha)-VI levels and the extent of atherosclerosis in ApoE-deficient mice: modulation by vitamin E. Blood. 2001 Jan 15;97(2):459-64. Abstract

4. Praticò D, Rokach J, Tangirala RK. Brains of aged apolipoprotein E-deficient mice have increased levels of F2-isoprostanes, in vivo markers of lipid peroxidation. J Neurochem. 1999 Aug;73(2):736-41. Abstract

5. Chinnici CM, Yao Y, Ding T, Funk CD, Praticò D. Absence of 12/15 lipoxygenase reduces brain oxidative stress in apolipoprotein E-deficient mice. Am J Pathol. 2005 Nov;167(5):1371-7. Abstract

6. Masliah E, Samuel W, Veinbergs I, Mallory M, Mante M, Saitoh T. Neurodegeneration and cognitive impairment in apoE-deficient mice is ameliorated by infusion of recombinant apoE. Brain Res. 1997 Mar 21;751(2):307-14. Abstract

7. Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer's disease. Annu Rev Neurosci. 1996;19:53-77. Abstract

View all comments by Domenico Pratico

Comment by Mark A. Smith, Xiongwei Zhu, Hyoung-gon Lee, Rudy J. Castellani, Jesus Avila, Massimo Tabaton, Lawrence M. Sayre, George Perry

Peroxidation in Alzheimer Disease: Time to Put the Ducks in a Row
Oxidative stress, including carbonyl lipid peroxidation adducts such as 4-hydroxynonenal (HNE), is now well established in the etiopathogenesis of Alzheimer disease (AD). However, for many investigators, the importance of oxidative stress has been relegated to one of consequence rather than cause. Such linearity of thought largely ignored the wealth of data showing that oxidative stress precedes pathology in AD (Nunomura et al., 2001) and in transgenic mice models of AD (Pratico et al., 2001). Further, oxidative stress regulates both tau phosphorylation (Takeda et al., 2000) and aggregation (Avila, 2000) as well as amyloid production (Yan et al., 1995), likely through regulation of the β- and γ-secretase machinery (Tamagno et al., 2002; Tamagno et al., 2005; Tamagno et al., 2008).

While the aforementioned data clearly show that oxidative stress can be...  Read more

Comment by Mark A. Smith, Xiongwei Zhu, Hyoung-gon Lee, Rudy J. Castellani, Jesus Avila, Massimo Tabaton, Lawrence M. Sayre, George Perry

Peroxidation in Alzheimer Disease: Time to Put the Ducks in a Row
Oxidative stress, including carbonyl lipid peroxidation adducts such as 4-hydroxynonenal (HNE), is now well established in the etiopathogenesis of Alzheimer disease (AD). However, for many investigators, the importance of oxidative stress has been relegated to one of consequence rather than cause. Such linearity of thought largely ignored the wealth of data showing that oxidative stress precedes pathology in AD (Nunomura et al., 2001) and in transgenic mice models of AD (Pratico et al., 2001). Further, oxidative stress regulates both tau phosphorylation (Takeda et al., 2000) and aggregation (Avila, 2000) as well as amyloid production (Yan et al., 1995), likely through regulation of the β- and γ-secretase machinery (Tamagno et al., 2002; Tamagno et al., 2005; Tamagno et al., 2008).

While the aforementioned data clearly show that oxidative stress can be causative, this paper by Ohta and colleagues (Ohsawa et al., 2008) hopefully represents a turning point since it clearly shows that the accumulation of HNE is sufficient to produce AD-like pathogenesis in a transgenic mouse. While not complete, it is certainly superior, in terms of spectrum, to single amyloid or tau models. Given the multifactorial nature of AD, an oxidative hit (Zhu et al., 2004; Zhu et al., 2007) is almost becoming obligate to any theory. It is time to recognize cause from consequence and that the failure of antioxidant intervention in disease modification is more likely a consequence of a lack of effect on oxidative balance (Thomas Montine, personal communication) than of a negligible role for oxidative stress in disease pathogenesis.

References:
Avila J (2000) Tau aggregation into fibrillar polymers: tauopathies. FEBS Lett 476(1-2): 89-92. Abstract

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 (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60(8): 759-67. Abstract

Ohsawa I, Nishimaki K, Murakami Y, Suzuki Y, Ishikawa M, Ohta S (2008) Age-dependent neurodegeneration accompanying memory loss in transgenic mice defective in mitochondrial aldehyde dehydrogenase 2 activity. J Neurosci 28(24): 6239-49. Abstract

Pratico D, Uryu K, Leight S, Trojanowski JQ, Lee VM (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21(12): 4183-7. Abstract

Takeda A, Smith MA, Avila J, Nunomura A, Siedlak SL, Zhu X, Perry G, Sayre LM (2000) In Alzheimer's disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification. J Neurochem 75(3): 1234-41. Abstract

Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M (2002) Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 10(3): 279-88. Abstract

Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, Muraca G, Danni O, Zhu X, Smith MA, Perry G, Jo DG, Mattson MP, Tabaton M (2008) Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem 104(3): 683-95. Abstract

Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, Perry G, Tabaton M (2005) Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem 92(3): 628-36. Abstract

Yan SD, Yan SF, Chen X, Fu J, Chen M, Kuppusamy P, Smith MA, Perry G, Godman GC, Nawroth P, et al. (1995) Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med 1(7): 693-9. Abstract

Zhu X, Lee HG, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 1772(4): 494-502. Abstract

Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer's disease: the two-hit hypothesis. Lancet Neurol 3(4): 219-26. Abstract

View all comments by Jesus Avila
View all comments by Rudy Castellani
View all comments by Hyoung-gon Lee
View all comments by George Perry
View all comments by Lawrence M. Sayre
View all comments by Mark A. Smith
View all comments by Massimo Tabaton
View all comments by Xiongwei Zhu