. Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5. PubMed.


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  1. New findings by Yao, Brinton, and colleagues strengthen the argument for a central role of mitochondrial abnormalities in contributing to AD pathogenesis. The investigators present compelling data indicating that indices of mitochondrial dysfunction and oxidative stress occur early in the development of pathology in female 3xTg-AD mice. Although the most significant differences between 3xTg-AD and non-Tg mice generally occur at age 12 months when Aβ pathology is robust, it is noteworthy that some changes occur at even the youngest age examined (three months) when Aβ immunoreactivity is sparse. Such findings suggest that Aβ deposition may occur subsequent rather than prior to significant mitochondrial impairment. The researchers’ observation that cultures from embryonic 3xTg-AD mice also exhibited evidence of mitochondrial dysfunction further supports early mitochondrial involvement in pathology since increased levels of Aβ likely do not occur in this transgenic model at such an early stage of development.

    Another interesting finding from this study is the age-related increase in markers of oxidative stress and mitochondrial dysfunction in non-Tg female mice. Significant changes in some indices are apparent by 9-12 months, a time corresponding to the onset of changes in the reproductive system of female mice that culminate in reproductive senescence. Given the hypothesized role of sex steroid hormones in regulating AD pathology, further understanding of hormonal regulation of mitochondrial function in both non-Tg and AD mouse models is of interest.

  2. I think this is an interesting paper which is consistent with a number of other published studies. The present data are of great interest in that they show that mitochondrial dysfunction precedes the amyloid pathology and NFTs in this triple mutation transgenic mouse model of AD. Other studies showed that oxidative stress precedes amyloid deposition (Pratico et al., 2001). They found decreased PDH and cytochrome oxidase activity, which are consistently found to be decreased in AD postmortem brain tissue. The etiology is most consistent with a direct effect of amyloid within mitochondria. Direct studies looking for mtDNA mutations have been largely negative, despite the ability to produce deficits in cybrid cell lines. We have replicated findings of increased production of free radicals in another transgenic mouse model of AD, and we found that antioxidants activating the nrf2/ARE pathway diminish amyloid pathology, as does overexpression of manganese superoxide dismutase (SOD2), which is confined to mitochondria. Congruent with this, we and others found that a reduction of SOD2 exacerbates amyloid and tau pathology. We and others also found that mitochondrial targeted antioxidants are efficacious. There is also impaired mitochondrial fission and fusion in AD (Wang et al., 2009). All together, there is increasing evidence that mitochondrial dysfunction may play a pivotal role in AD pathogenesis.


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

    . Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. PubMed.

  3. The authors have observed an interesting pathogenic change in the 3xTg-AD female brain in that a mitochondrial deficit preceded the amyloid pathology. I agree with their observations, and have this question: What induced the mitochondrial impairment? Our observations suggest homocysteic acid (HA). HA is produced from homocysteine by cystathionine β-synthase (CBS), whose activity is dependent on calcium, or lipid peroxide, and HA production with CBS is dependent on B6 deficiency. The 3xTg-AD model mice express three transgenes—APP, presenilin, and tau. Presenilin is reported to activate calcium inflow into the cell; HA production is stimulated by presenilin activation. This result was observed by us (submitted for publication).

    Given that anti-amyloid treatments have not been successful so far, Brinton and colleagues' observations suggest estrogen-based and mitochondrial treatment as alternatives; our observations suggest treatment for HA as a possible new target to develop.

    View all comments by Tohru Hasegawa

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