Mice with a defect in a mitochondrial dehydrogenase enzyme, a defect that leads to a buildup of toxic aldehydes, show age-related neurodegeneration with several features of late-onset Alzheimer disease. Generated in the lab of Shigeo Ohta of the Nippon Medical School in Kawasaki, Japan, the mice carry a mutated form of mitochondrial aldehyde dehydrogenase 2 (ALDH2). They show neuronal loss, tau hyperphosphorylation, cognitive impairment, and die earlier than wild-type. The results suggest that oxidative stress and, in particular, toxic aldehydes, which have been shown to accumulate in the brain in AD, could play a key role in neurodegeneration, and that ALDH2 may protect against them. The work appears in the June 11 issue of the Journal of Neuroscience.

ALDH2 is best known for its role in alcohol metabolism. Ethanol is converted to acetaldehyde by an alcohol dehydrogenase, and ALDH2 then oxidizes most of that acetaldehyde into acetate. A point mutation in the ALDH2 gene in some Asians results in enzyme deficiency, and the resulting accumulation of ethanol-derived acetaldehyde in the bloodstream leads to a flushing reaction that produces the bright red faces some people develop upon imbibing. “Most people believe that the physiological role of ALDH2 is to detoxify acetaldehyde derived from ethanol,” Ohta explained to ARF by e-mail. “On the other hand, we have proposed that ALDH2 detoxifies toxic aldehydes derived from lipid peroxides and functions as a protector against oxidative stress.”

Among those lipid-derived aldehydes is 4-hydoxy-2-nonenal (HNE), a lipid-derived synaptotoxin whose production is stimulated by amyloid-β and is elevated in AD brain (see ARF related news story and a recent review by Reed et al., 2008). Previous work from Ohta and colleagues showed that women with ALDH2 deficiency had a higher level of lipid peroxides in their blood (Ohsawa et al., 2003), and that ALDH2 deficiency may be a risk factor for late-onset AD in Japanese, in conjunction with the ApoE4 allele (Kamino et al., 2000, and see Alzgene entry).

To look at the effects of ALDH2 deficiency in brain, first author Ikuroh Ohsawa and colleagues made transgenic mice expressing the mouse equivalent of the human mutation, which functions as a dominant-negative inhibitor of ALDH2 activity. Neurons from those mice were more vulnerable to the toxic effects of HNE, and in vivo, the mice showed an age-dependent buildup of HNE in their brains.

Along with a shorter lifespan (96 weeks versus 126 weeks for wild-type mice), and evidence of enhanced oxidative stress, the ALDH2-deficient mice developed age-dependent neurodegeneration. Twenty percent of the mice showed neuronal loss in pyramidal neurons of the hippocampus at one year of age, which rose to nearly 80 percent at 1.5 years old. More than half of the mice developed neuroinflammation, and nearly half showed AT8 (serine 202) tau hyperphosphorylation in the same neurons. Aged, but not young, mice showed memory deficits in an object recognition task and the Morris water maze, two hippocampal-dependent tests.

Because their previous work showed a possible genetic interaction between ALDH2 and ApoE in humans, and the fact that ApoE binds HNE and can prevent its toxicity in cells (Pedersen et al., 2000), the investigators looked at the effect of ApoE status on memory performance in the ALDH2 mutant mice. By six months old, ApoE knockout/ALDH2 mutant mice showed cognitive deficits in the Morris water maze, which were not seen with either parental line.

“This paper shows evidence that the accumulation of 4-HNE (4-hydroxy-2-nonenal), one of the toxic aldehydes, is sufficient to exhibit age-dependent neuronal degeneration,” Ohta told ARF. “Thus, in order to prevent age-dependent neurodegenerative disorders including Alzheimer’s disease, the paper suggests that it is critical to prevent accumulations of lipid peroxides by suitable antioxidants upstream of accumulation of toxic aldehydes derived from the lipid peroxides. Alternatively, it may be important to stimulate alternative pathways to detoxify 4-HNE, such as glutathione S-transferase, aldo-keto reductase, amyloid-β peptide binding alcohol dehydrogenase, downstream of accumulation of toxic aldehyde,” he said.—Pat McCaffrey


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  1. 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.


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    . 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. PubMed.

    . 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. PubMed.

    . Absence of 12/15 lipoxygenase reduces brain oxidative stress in apolipoprotein E-deficient mice. Am J Pathol. 2005 Nov;167(5):1371-7. PubMed.

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    View all comments by Domenico Pratico
  2. 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.


    . Tau aggregation into fibrillar polymers: taupathies. FEBS Lett. 2000 Jun 30;476(1-2):89-92. PubMed.

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

    . Age-dependent neurodegeneration accompanying memory loss in transgenic mice defective in mitochondrial aldehyde dehydrogenase 2 activity. J Neurosci. 2008 Jun 11;28(24):6239-49. PubMed.

    . Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci. 2001 Jun 15;21(12):4183-7. PubMed.

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    . Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem. 2008 Feb;104(3):683-95. PubMed.

    . Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem. 2005 Feb;92(3):628-36. PubMed.

    . 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. 1995 Jul;1(7):693-9. PubMed.

    . Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta. 2007 Apr;1772(4):494-502. PubMed.

    . Alzheimer's disease: the two-hit hypothesis. Lancet Neurol. 2004 Apr;3(4):219-26. PubMed.

    View all comments by Jesus Avila


News Citations

  1. Aβ—Three Places, Three Ways of Wreaking Havoc

Paper Citations

  1. . Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer's disease. Neurobiol Dis. 2008 Apr;30(1):107-20. PubMed.
  2. . Genetic deficiency of a mitochondrial aldehyde dehydrogenase increases serum lipid peroxides in community-dwelling females. J Hum Genet. 2003;48(8):404-9. PubMed.
  3. . Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population. Biochem Biophys Res Commun. 2000 Jun 24;273(1):192-6. PubMed.
  4. . A mechanism for the neuroprotective effect of apolipoprotein E: isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal. J Neurochem. 2000 Apr;74(4):1426-33. PubMed.

External Citations

  1. Alzgene entry

Further Reading


  1. . Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer's disease. J Cell Mol Med. 2008 Jun;12(3):987-94. PubMed.
  2. . A neuronal model of Alzheimer's disease: an insight into the mechanisms of oxidative stress-mediated mitochondrial injury. Neuroscience. 2008 Apr 22;153(1):120-30. PubMed.
  3. . Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer's disease. Neurobiol Dis. 2008 Apr;30(1):107-20. PubMed.

Primary Papers

  1. . Age-dependent neurodegeneration accompanying memory loss in transgenic mice defective in mitochondrial aldehyde dehydrogenase 2 activity. J Neurosci. 2008 Jun 11;28(24):6239-49. PubMed.