An enzyme that breaks down alcohols in mitochondria also binds Aβ, and new research suggests that disrupting this interaction protects waning mitochondria and improves spatial memory in a mouse model of Alzheimer’s disease. Mitochondria in treated animals accumulated less Aβ and stepped up activity of the Aβ-degrading enzyme pre-sequence peptidase. Shirley ShiDu Yan of Columbia University, New York, and colleagues reported the findings in this week’s Journal of Neuroscience.

“The authors have developed a potential new AD therapeutic and made a good case for testing their novel approach in humans,” commented Russell Swerdlow, University of Kansas School of Medicine, Kansas City. Previously, Swerdlow led an Alzforum Live Discussion on the links between mitochondrial dysfunction and sporadic AD. “It’s not every day that you encounter basic research with such obvious translational implications,” he wrote in an e-mail to ARF (see full comment below).

The current paper extends earlier work by Yan and collaborator Hao Wu of Weill Cornell Medical College, New York (Lustbader et al., 2004). That study found that mitochondrial Aβ binds Aβ peptide-binding alcohol dehydrogenase (ABAD) in a manner that excludes nicotinamide adenine dinucleotide (NAD), an ABAD cofactor. Furthermore, the research suggested that the Aβ-ABAD interaction could matter functionally. Overexpression of ABAD drove up neuronal production of free radicals and worsened memory problems in J20 APP transgenic mice. In addition, the scientists designed an antagonist peptide targeting ABAD’s Aβ-binding region and showed it could relieve oxidative stress and prevent apoptosis in cultured wild-type neurons (see ARF related news story).

Now, first author Jun Yao and colleagues show this antagonist peptide works in vivo. They used two approaches—injecting it into adult APP transgenic mice (J20), and creating double transgenic J20 mice that overexpress the antagonist from birth. Previously, the scientists fused the ABAD antagonist peptide, or its reverse version as a control, to an 11-amino-acid transduction domain of human immunodeficiency virus 1 transactivator protein (HIV Tat), which speeds the peptide’s entry into cells. For the present study, Yan’s team also included a mitochondrial targeting sequence in their constructs.

Once a day for three months, the researchers injected this mitochondria-targeted ABAD antagonist intraperitoneally into the J20 transgenic mice. They started the regimen at seven months of age, when the mice show mild behavioral impairment but not yet severe mitochondrial damage. By immunoblotting, the scientists showed that the ABAD antagonist, but not the reverse peptide, blocked formation of ABAD-Aβ complexes in brain mitochondria of treated AD mice. The treatment preserved mitochondrial function, as judged by various parameters including respiratory rate and generation of reactive oxygen species. Importantly, this helped the treated AD mice do as well as vehicle-treated and reverse peptide-treated non-transgenic controls in the radial arm water maze, which tests spatial memory.

To confirm these benefits, the scientists generated transgenic mice that overexpress, in addition to APP, the mitochondria-targeted ABAD antagonist in cortical neurons. These animals formed less Aβ-ABAD complex, fewer reactive oxygen species, and their mitochondria functioned better than was the case in non- and single-transgenic controls. At 10-12 months of age, when AD mice show clear spatial learning deficits in the radial arm maze, the double-transgenic animals performed comparably to wild-type mice and single transgenics overexpressing the mitochondria-targeted ABAD antagonist.

A bonus came when the team analyzed cortical mitochondrial fractions from double-transgenic and ABAD antagonist-treated AD mice. They found reduced Aβ levels. Given that Aβ gets degraded by the mitochondrial pre-sequence peptidase (Falkevall et al., 2006 and ARF related news story), the authors checked the activity of the enzyme in isolated brain mitochondria. Lo and behold! It was up in cortical mitochondria from double-transgenic mice. “We think this may be one of the mechanisms for why Aβ is decreased in these animals,” Yan told ARF. Pre-sequence peptidase degrades proteins smaller than 70 amino acids, including soluble Aβ. But when Aβ binds endogenous ABAD, the resulting complex exceeds the 70-amino-acid cut-off, perhaps allowing Aβ to escape degradation. Thus, the antagonist may work by preventing formation of the Aβ-ABAD complex, leaving Aβ available for peptidase degradation, Yan proposed.

All told, “the results strongly implicate a critical role for mitochondrial Aβ in AD pathogenesis,” noted M. Flint Beal of Weill Cornell Medical College in New York, in an e-mail to ARF. “The paper is also of interest in that it shows a means of getting peptides into brain mitochondria following systemic administration using a Tat peptide and a mitochondrial targeting sequence. It would be of interest to see if a similar approach would have efficacy in other species like aged primates, and whether tau pathology can be prevented using this approach,” he wrote (see full comment below).

Yan said her lab is currently screening for compounds that inhibit the Aβ-ABAD interaction in mitochondria. In addition, the researchers are working to modify previously identified small-molecule inhibitors of ABAD-Aβ binding (Xie et al., 2006) to improve their potency, stability, and access to brain mitochondria.—Esther Landhuis.

Reference:
Yao J, Du H, Yan S, Fang F, Wang C, Lue LF, Guo L, Chen D, Stern DM, Moore FJ, Chen JX, Arancio O, Yan SS. Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer’s disease. J. Neurosci. 9 Feb 2011;31(6):2313-2320. Abstract

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Comments on News and Primary Papers

  1. In this paper, the Yan lab does a remarkable job following up on its seminal 2004 work that showed Aβ and an alcohol dehydrogenase associate within the mitochondria of mutant APP transgenic mice. The findings in this current paper reinforce the view that a mitochondrial-Aβ nexus is functionally important, at least in these mice. The authors extend the original finding to further make the point that mitochondrial mechanisms, such as the PreP protein, may have evolved to regulate mitochondrial Aβ levels and dynamics. In the process, the authors have developed a potentially new and novel AD therapeutic, and made a good case for testing their novel therapeutic approach in humans. It's not everyday you encounter what is essentially basic research that has such obvious translational implications.

    View all comments by Russell Swerdlow
  2. This is an impressive amount of work done by Dr. Yan and colleagues. The results strongly implicate a critical role for Aβ in mitochondria for AD pathogenesis. The finding that blocking the interaction of Aβ with Aβ peptide-binding alcohol dehydrogenase also leads to a reduction in Aβ levels due to degradation by PreP is also intriguing. The use of the reverse decoy peptide is an excellent control. The paper is also of interest in that it shows a means of getting peptides into brain mitochondria following systemic administration using a Tat peptide and a mitochondrial targeting sequence. It would be of interest to see if a similar approach would have efficacy in other species like aged primates, and whether tau pathology can be prevented using this approach.

    View all comments by Flint Beal

References

Webinar Citations

  1. A "Mitochondrial Cascade Hypothesis" for Sporadic Alzheimer's Disease

News Citations

  1. ABAD, aka ERAB: Mitochondrial Miscreant Returns
  2. Novel Aβ Protease Found in Mitochondria

Paper Citations

  1. . ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science. 2004 Apr 16;304(5669):448-52. PubMed.
  2. . Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem. 2006 Sep 29;281(39):29096-104. PubMed.
  3. . Identification of small-molecule inhibitors of the Abeta-ABAD interaction. Bioorg Med Chem Lett. 2006 Sep 1;16(17):4657-60. PubMed.
  4. . Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease. J Neurosci. 2011 Feb 9;31(6):2313-20. PubMed.

Other Citations

  1. J20 APP transgenic mice

Further Reading

Papers

  1. . Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med. 2008 Oct;14(10):1097-105. PubMed.
  2. . Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease. J Neurosci. 2011 Feb 9;31(6):2313-20. PubMed.
  3. . ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science. 2004 Apr 16;304(5669):448-52. PubMed.
  4. . Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem. 2006 Sep 29;281(39):29096-104. PubMed.

Primary Papers

  1. . Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease. J Neurosci. 2011 Feb 9;31(6):2313-20. PubMed.