20 June 2008. 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.
Ohsawa I, Nishimaki K, Murakami Y, Suzuki Y, Ishikawa M, Ohta S. 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. Abstract