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21 August 2009. The energy needs of neurons are prodigious—the brain makes up just a small percentage of the body, yet burns roughly 25 percent of its calories (Leonard et al., 2007). That hunger for energy requires that mitochondria stay in tip-top shape, and indeed, a drop-off in their function is associated with Alzheimer disease, Parkinson disease, and other neurodegenerative conditions (for a review, see Reddy and Beal, 2008). Now, a study from Roberta Diaz Brinton and colleagues at the University of Southern California, Los Angeles, shows that flagging energy generation starts very early and gets worse with age in a mouse model of AD. In a paper published August 10 in PNAS online, Brinton and coworkers report mitochondrial deficits in embryonic neurons from female mice expressing a trio of AD-related proteins. The observed malfunction of mitochondria worsens when the animals reach reproductive senescence (the mouse equivalent of human menopause). The results indicate that mitochondrial problems begin long before amyloid deposition begins, and thus may be a causal contributor to the development of AD pathology in these mice. In addition, the coincident timing of estrogen loss and worsening mitochondrial dysfunction suggests that the neuroprotective actions of estrogen may stem from its ability to preserve brain energetics.
Women account for 68 percent of cases of AD, and one commonly offered explanation for their overrepresentation is that they simply live longer than men do and so have a greater age-related risk of developing dementia. However, Brinton told ARF she thinks there is more to it. Her previous work showed that estrogen keeps mitochondria ticking along, and loss of estrogen causes a 20-30 percent drop in glucose metabolism and mitochondrial function (Irwin et al., 2008). AD is also associated with lower levels of some mitochondrial enzymes, lower glucose uptake, and higher oxidative stress, so Brinton wondered what it means to lose 30 percent of one’s bioenergy portfolio. Could a drop in mitochondrial function at menopause be contributing to AD?
To understand that question better, first author Jia Yao studied lifetime mitochondria function in triple transgenic AD mice (Oddo et al., 2003). The mice express three mutated AD-related proteins—amyloid precursor protein, tau, and presenilin—and develop progressive amyloid and tau pathology. Yao found that as early as three months of age, the animals already showed significant decreases in glucose metabolism (lower levels of pyruvate dehydrogenase protein), and higher production of harmful free radicals and lipid peroxidation. Other indictors of mitochondrial function (cyclooxygenase activity, hydrogen peroxide production, and decreased respiration) were significantly lowered later, ranging from six to 12 months.
Mitochondrial function also decreased with age in normal mice, but the decline overall was steeper in the AD mice. The differences between normal and transgenic animals were greatest after nine months, when the mice enter reproductive senescence. This also corresponded to the time when Aβ appeared in the mitochondria, as measured by Western blot for a 16 kDa Aβ oligomer, or as the Aβ-alcohol dehydrogenase complex previously implicated in mitochondrial dysfunction (see ARF related news story on Lustbader et al., 2004). This is consistent with much previous work showing that loss of estrogen cranks up amyloid production, including specifically in the 3xTg mice (Carroll et al., 2007).
The results at three months indicated that mitochondria were malfunctioning before significant amyloid pathology appeared. The researchers wanted to know when the trouble started, so they looked at cultured embryonic hippocampal neurons. Even at that early time, they found decreased oxygen consumption and increased glycolysis. When they measured mitochondrial capacity by treating the cells with a mitochondrial uncoupler, the researchers found that cells from the transgenic mice revealed a lower overall respiratory capacity than did normal mice. “The AD mouse simply cannot rise to the metabolic challenge,” Brinton says. This may bode poorly for the neurons as their energy demands increase, though just why the mitochondria are affected is unclear. “It has to be one of the three transgenes, and that is something we are testing right now,” she said.
“The most important finding is that a metabolic mitochondrial deficit precedes the development of AD pathology, by a substantial amount of time, suggesting that there is a slow inexorable deficit in the bioenergetics in the brain that leads to development of AD pathology,” Brinton says. The results are consistent with epidemiological observation that children whose mothers had AD are at a higher risk for the disease whether they are male or female. Since mitochondrial genes are inherited through the maternal line, that suggests that some of those genes may predispose to AD, possibly by affecting energy metabolism (Mosconi et al., 2009).
The results also provide a potential explanation for the neuroprotective effects of estrogen, and a rationale for using the hormone to protect mitochondria. Early epidemiological studies indicated that women on hormone replacement therapy had lower risk for developing AD. Later, the Women’s Health Study showed the opposite (see ARF live discussion), but those women started estrogen at age 65, not at menopause as in the earlier studies. Since then, additional work has shown that women who have their ovaries removed pre-menopausally have an increased risk of AD and Parkinson disease (see ARF related news story on Rocca et al, 2007). Is this due to effects of estrogen on mitochondria? That is not clear, but Brinton says that they are currently testing the idea that estrogen depletion acts via mitochondria to promote AD pathology in mouse models.
“The data suggest that the time to intervene to increase estrogen is not at the time of AD diagnosis, but at the time of loss of estrogen," says Brinton. “We need to take seriously this window of opportunity for a prevention strategy.” One idea Brinton’s lab and others are working on is brain-selective estrogen receptor modulators that target the estrogen receptor B, which is present in brain but low in other estrogen target tissues including breast and uterus (Tiwari-Woodruff et al., 2007; Zhao et al, 2007). Closer to the clinic is an estrogen receptor β-selective plant-based phytoestrogen preparation that Brinton is planning to test for the prevention of hot flashes in menopausal women. If that works, it may provide an alternative strategy to fine-tune estrogen replacement for the benefit of the brain.—Pat McCaffrey.
Reference:
Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Aug 10. Abstract
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Primary Papers: Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.
Comment by: Christian Pike
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Submitted 21 August 2009
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Posted 21 August 2009
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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...
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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.
 View all comments by Christian Pike |
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Primary Papers: Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.
Comment by: M. Flint Beal
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Submitted 21 August 2009
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Posted 21 August 2009
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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,...
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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.
View all comments by M. Flint Beal |
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Primary Papers: Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.
Comment by: George Perry (Disclosure)
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Submitted 20 August 2009
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Posted 25 August 2009
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 I recommend this paper
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Comment by: Tohru Hasegawa
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Submitted 25 August 2009
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Posted 25 August 2009
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I recommend the Primary Papers
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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Comments on Related News |
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Related News: AD Therapeutic Approaches Tap Complement, Mitochondrial Antioxidant
Comment by: P. Hemachandra Reddy
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Submitted 17 August 2009
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Posted 17 August 2009
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The findings of Massaad and colleagues will advance our basic understanding of the neuroprotective role of mitochondrially targeted antioxidants in Alzheimer disease (AD) pathogenesis. Their findings suggest that mitochondrial superoxide dismutase 2 (SOD2) decreases hippocampal superoxide radicals, ameliorates learning/memory deficits, and decreases amyloid-β (Aβ) plaques in double transgenic mice that overexpress SOD2 and mutant human amyloid precursor protein. Interestingly, they also found a decreased ratio of Aβ1-42 to 1-40 in double transgenic mice. These findings further support the mitochondrial oxidative damage hypothesis of AD, and may have important implications for mitochondrially targeted antioxidant therapeutics in AD.
Increasing evidence suggests that mitochondrial abnormalities are involved in the development and progression of AD (reviewed in Reddy, 2009). Further, it has been proposed that mitochondrially generated free radicals and oxidative damage are involved in abnormal processing of APP and in generating Aβ peptide by activating...
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The findings of Massaad and colleagues will advance our basic understanding of the neuroprotective role of mitochondrially targeted antioxidants in Alzheimer disease (AD) pathogenesis. Their findings suggest that mitochondrial superoxide dismutase 2 (SOD2) decreases hippocampal superoxide radicals, ameliorates learning/memory deficits, and decreases amyloid-β (Aβ) plaques in double transgenic mice that overexpress SOD2 and mutant human amyloid precursor protein. Interestingly, they also found a decreased ratio of Aβ1-42 to 1-40 in double transgenic mice. These findings further support the mitochondrial oxidative damage hypothesis of AD, and may have important implications for mitochondrially targeted antioxidant therapeutics in AD.
Increasing evidence suggests that mitochondrial abnormalities are involved in the development and progression of AD (reviewed in Reddy, 2009). Further, it has been proposed that mitochondrially generated free radicals and oxidative damage are involved in abnormal processing of APP and in generating Aβ peptide by activating β- and γ-secretases (Reddy, 2006; Reddy and Beal, 2008). There is some evidence to support this hypothesis (Tamagno et al., 2008; Jin et al., 2008). Further, recently several groups (Crouch et al., 2005; Caspersen et al., 2005; Manczak et al., 2006; Devi et al., 2006; Hanson Petersen et al., 2008) found that Aβ peptide is localized to mitochondrial membranes and the mitochondrial matrix, and that mitochondrially localized Aβ peptide interacts with mitochondrial proteins, induces free radical production, decreases cytochrome oxidase activity, inhibits ATP production, and damages AD neurons. In addition, recent structural studies revealed that Aβ fragments mitochondria, suggesting that mitochondrial structural abnormalities (caused by Aβ) may be critical for mitochondrial dysfunction in AD (Wang et al., 2009; Mao et al., 2009). Overall, these studies suggest that Aβ and mitochondrial dysfunction play a big role in AD pathogenesis.
To determine the role of overexpressed SOD2 in AD pathogenesis, Massaad et al. crossed SOD2 transgenic mice with Tg2576 mice and studied cognitive deficits, Aβ1-42 and 1-40 levels, and Aβ deposits in Tg2576 mice and double mutant mice (SOD2xTg2576 mice). They found decreased Aβ deposits and reduced cognitive deficits in double transgenic mice relative to Tg2576 mice, suggesting that mitochondrial superoxide dismutase improves cognitive functions in AD. However, it is still unclear 1) how overexpressed mitochondrial superoxide dismutase alters the ratio of Aβ1-42 to 1-40; and 2) how overexpressed mitochondrial superoxide dismutase improves learning and memory functions in double mutant mice. Further research is needed to find answers to these questions, and the answers may have some important implications to AD patients.
Overall, findings of the study by Massaad and colleagues, together with previous studies (Hirai et al., 2001; Swerdlow et al., 1997; Reddy et al., 2004; Manczak et al., 2004; Caspersen et al., 2005; Manczak et al., 2006; Devi et al., 2006; Hansson Petersen et al., 2008; Wang et al., 2009), improve our understanding of mitochondrial oxidative damage in AD pathogenesis. Given the limited success of recent clinical trials using natural antioxidants in AD patients, findings from this new study may have some important implications for the development of mitochondrially targeted therapeutics for AD patients.
References:
Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005 Dec;19(14):2040-1. Abstract
Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006 Aug 30;26(35):9057-68. Abstract
Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, Leinonen V, Ito A, Winblad B, Glaser E, Ankarcrona M. 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. Epub 2008 Aug 29. Abstract
Hirai K, Aliev G, Nunomura A, Fujioka H, Russel RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Peterson RB, Perry G, Smith MA. Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. Abstract
Jin SM, Cho HJ, Jung ES, Shim MY, Mook-Jung I. DNA damage-inducing agents elicit gamma-secretase activation mediated by oxidative stress. Cell Death Differ. 2008 Sep;15(9):1375-84. Epub 2008 Apr 18. Abstract
Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of Abeta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006 May 1;15(9):1437-49. Abstract
Manczak M, Park B, Jung Y, Reddy PH. Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 2004;5(2):147-62. Abstract
Mao P, Manczak M, Shree D and Reddy PH. Abnormal mitochondrial structural and functional changes caused by amyloid beta in Alzheimer’s disease. Paper presented at the International Conference on Alzheimer’s disease held Vienna, Austria July 11-16, 2009.
Reddy PH. Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease.
J Neurochem. 2006 Jan;96(1):1-13. Abstract
Reddy PH. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease.Exp Neurol. 2009 Aug;218(2):286-92. Abstract
Reddy PH Beal MF. 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. Abstract
Reddy PH, McWeeney S, Park BS, Manczak M, Gutala RV, Partovi D, Jung Y, Yau V, Searles R, Mori M Quinn J. Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum Mol Genet. 2004 Jun 15;13(12):1225-40. Abstract
Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP Jr., Davis RE, Parker WD Jr. Cybrids in Alzheimer's disease: a cellular model of the disease? Neurology. 1997;49:918-925. Abstract
Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, Muraca G, Danni O, Zhu X, Smith MA, Perry G, Jo DG, Mattson MP, Tabaton M. 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. Abstract
Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. Abstract
View all comments by P. Hemachandra Reddy |
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