Two papers out this week focus on mitochondria in neurodegeneration in general and Alzheimer disease in particular. One, from Hiroshi Nakanishi, Tomomi Ide, and colleagues, Kyushu University, Fukuoka, Japan, presents evidence that the mitochondrial Transcription factor A (TFAM), known for its protective effects on mitochondrial DNA, can prevent age-dependent memory impairment and loss of neuronal function when overexpressed in transgenic mice. TFAM works, they propose, by reducing oxidative stress and mitochondrial dysfunction mainly in microglia. The work, which appears in the August 20 issue of the Journal of Neuroscience, links mitochondrial impairment to the cognitive decline of aging, and suggests that finding ways to protect mitochondria could provide an anti-aging effect for the brain.

Mitochondria also loom large in the cellular toxicity of the amyloid peptide Aβ in Alzheimer disease (for a recent review see Reddy and Beal, 2008). The second paper, out in this week’s PNAS online from investigators Maria Ankarcrona of the Karolinska Institute and Elzbieta Glaser of Stockholm University, both in Sweden, provides an explanation for how Aβ accumulates in mitochondria. Their data indicate that Aβ can be imported by the translocase of the outer membrane (TOM) system, and accumulates on inner mitochondrial membranes. The location of Aβ on cristae places it in proximity to the electron transport chain enzymes, which the same researchers previously showed were inhibited in vitro by the peptide (Crouch et al., 2005).

Aging is associated with mitochondrial decline, involving increased generation of reactive oxygen, damage to respiratory chain proteins and mitochondria DNA, and a decrease in mitochondrial energy generation, which can lead to neurodegeneration. TFAM, a factor that drives transcription of genes encoded by mitochondrial DNA, is also known to protect mtDNA from oxidative damage. Loss of TFAM in dopaminergic neurons in mice results in Parkinson disease-like neuronal loss (see ARF related news story), and the gene was recently implicated in epigenetic changes that occur in aging (see ARF related news story).

To ask if TFAM affects oxidative stress, the researchers, led by first authors Yoshinori Hayashi, Masayoshi Yoshida, and Mayumi Yamato, first looked at the effects of overexpression of the protein in HeLa cells treated with the electron transport chain Complex I inhibitor rotenone. They found that TFAM expression reduced the production of reactive oxygen species (ROS) in response to rotenone, and also inhibited ROS-stimulated activation of the NF-κB transcription factor, a marker of oxidative stress.

To look at the impact of TFAM on oxidative stress in vivo and brain aging, the researchers measured oxidative damage and brain function in TFAM-overexpressing transgenic mice. In aged transgenic mice, boosting TFAM expression was associated with less lipid peroxidation, and higher activity of respiratory chain complexes I and IV, both of which normally decline with age.

The anti-aging effects of TFAM were apparent on several behavioral tests. When mice were put on a rotating rod facing backwards, they had to learn to turn and walk forward to avoid falling off. Old wild-type mice took longer to learn the skill than young mice, but the old TFAM transgenics showed no such age-dependent decline. Likewise, in a radial water maze test of working memory (the test combines features of the radial arm and Morris water mazes), the old TG mice learned better than wild-type. Finally, in electrophysiological measurements of long-term potentiation, a neural substrate for memory, the old transgenic mice retained a youthful response compared to the loss of LTP seen in their wild-type littermates.

The decline in cognitive function in wild-type aging mice tracked with increased markers of oxidative damage in the brain, including lipid and DNA oxidation, and the induction of the cytokine interleukin 1β (IL-1β) in microglia. These changes were not seen in the TFAM transgenics. To look at the possible relationship between IL-1β, oxidative damage and LTP, the investigators injected mice with lipopolysaccharide to induce inflammatory IL-1β expression. In the aged TFAM transgenics, IL-1β induction occurred, but at lower levels compared to wild-type mice. As IL-1β increased in the TFAM mice, however, there was a corresponding increase in oxidative damage and a decrease in LTP. “The present study clearly demonstrated a causal relationship among mitochondrial ROS, mitochondrial dysfunction and deficits in the brain functions during the process of aging,” the authors write. “Additional clarification of the mechanisms by which TFAM exhibits an antioxidant effect and maintains the mitochondrial function may eventually lead to the development of an anti-aging strategy to preserve brain function,” they conclude.

In Alzheimer disease, Aβ has been found in mitochondria, and in their PNAS paper, first authors Camilla Hansson Petersen and Nyosha Alikhani point a finger at a membrane translocase as the route of entry. The investigators found mitochondrial Aβ labeling in brain tissue specimens from neurosurgery patients with amyloidosis. They also found that when fluorescent Aβ was applied to neuronal cells in culture, it ended up in mitochondria. Using purified rat liver mitochondria, they demonstrated that the uptake did not depend on membrane potential, but instead was blocked by antibodies to components of the translocase of the outer membrane (TOM) machinery. Aβ did not block the entry pore, since other proteins could be imported even after exposure to Aβ. The Aβ appeared to end up in the inner membrane fraction of the mitochondria, based on cell fractionation experiments. Immunoelectron microscopy indicated that most of the Aβ was present in the cristae of the mitochondria. The inner membrane is where the respiratory chain enzymes reside, and the same group previously reported that Aβ42 inhibits activity of complex IV (Crouch et al., 2005), an action that could lead to generation of ROS. With the finding that mitochondria also harbor an Aβ-degrading enzyme (see ARF related news story), the results highlight the potential importance of Aβ in mitochondria as a possible inducer of mitochondrial dysfunction.—Pat McCaffrey

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  1. It's interesting that TFAM can prevent age-dependent memory impairment and loss of neuronal function when overexpressed in transgenic mice. Telmisartan increases expression of TFAM and MTOC1 and has been found to prevent cognitive decline following intracerebroventricular injection of Aβ1-40 (1,2).

    Perhaps further reason to suspect benefit with Telmisartan therapy in AD and ALS is provided by Baden and colleagues who report that Telmisartan inhibits methylglyoxal induced caspase-3 activation. Methylglyoxal has been implicated in the formation of amyloid plaques and neurofibrillary tangles in AD. Rohn suggests that caspase-cleaved TDP-43 is a major pathological finding in AD (3,4,5).

    References:

    . Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension. 2006 May;47(5):1003-9. PubMed.

    . Telmisartan prevented cognitive decline partly due to PPAR-gamma activation. Biochem Biophys Res Commun. 2008 Oct 24;375(3):446-9. PubMed.

    . Telmisartan inhibits methylglyoxal-mediated cell death in human vascular endothelium. Biochem Biophys Res Commun. 2008 Aug 22;373(2):253-7. PubMed.

    . Methylglyoxal, glyoxal, and their detoxification in Alzheimer's disease. Ann N Y Acad Sci. 2005 Jun;1043:211-6. PubMed.

    . Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer's disease. Brain Res. 2008 Sep 4;1228:189-98. PubMed.

  2. Mitochondrial dysfunction is an early event observed in the Alzheimer's brain. Recent studies have highlighted the role of mitochondrial Aβ in AD pathogenesis. We and others have demonstrated the presence of Aβ species in the mitochondria of both AD brain and transgenic AD mice overexpressing Aβ. Aβ progressively accumulates in mitochondria and links to mitochondrial malfunction. However, it is unclear how Aβ gets into mitochondria under physiological and pathological conditions. Our previous studies suggest that Aβ can translocate from the endoplasmic reticulum to the mitochondria, as we demonstrated that the addition of brefeldin A, an inhibitor of protein transport from the ER/intermediate compartment, significantly increased accumulation of mitochondrial Aβ. These data suggest that abnormalities in the secretory pathway may trigger pathologic accumulation of Aβ in mitochondria, potentially promoting mitochondrial dysfunction.

    The report by Dr. Hansson Petersen and colleagues further demonstrates that Aβ is imported to the mitochondria through the TOM pathway. These studies provide evidence that Aβ is able to get into mitochondria leading to mitochondrial dysfunction. Further, mitochondria may be a potential therapeutic target for treatment of AD. In addition, illustration of the unique systems involved in importation and proteolysis of Aβ in mitochondria may broaden our understanding on the basic biology of mitochondria.

    View all comments by Shirley ShiDu Yan

References

News Citations

  1. New Mouse Model Links Mitochondria to Parkinson Disease
  2. Drifting Toward AD—Epigenetic Changes Linked to Disease
  3. Novel Aβ Protease Found in Mitochondria

Paper Citations

  1. . Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 2008 Feb;14(2):45-53. PubMed.
  2. . Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42. J Neurosci. 2005 Jan 19;25(3):672-9. PubMed.

Further Reading

Primary Papers

  1. . Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice. J Neurosci. 2008 Aug 20;28(34):8624-34. PubMed.
  2. . The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13145-50. PubMed.