Age at onset: important marker of genetic heterogeneity in Alzheimer's disease

Martins, Ralph N.; Hallmayer, J.

doi:10.1038/sj.tpj.6500239

Cited by 8 publications

(5 citation statements)

References 9 publications

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“…Compromised activity of PDH and COX reduces the substrate input and driving force for oxidative phosphorylation, resulting in increased ATP demand via other pathways that leads to the activation of ketogenic pathway. Our findings of decreased activity of PDH and COX with reproductive senescence are consistent with the clinical observation of significantly decreased PDH and COX activity in postmortem Alzheimer’s brain tissue [28, 32]. …”

Section: Discussionsupporting

confidence: 91%

Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence

Yao

Hamilton

Cadenas

et al. 2010

Biochimica et Biophysica Acta (BBA) - General Subjects

136

140

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Background We have previously demonstrated that mitochondrial bioenergetic deficits precede Alzheimer’s pathology in the female triple transgenic Alzheimer’s (3xTgAD) mouse model. Herein, we sought to determine the impact of reproductive senescence on mitochondrial function in the normal non-transgenic (nonTg) and 3xTgAD female mouse model of AD. Methods Both nonTg and 3xTgAD female mice at 3,6,9, and 12 months of age were sacrificed and mitochondrial bioenergetic profile as well as oxidative stress markers were analyzed. Results In both nonTg and 3xTgAD mice, reproductive senescence paralleled a significant decline in PDH, and Complex IV cytochrome c oxidase activity and mitochondrial respiration. During the reproductive senescence transition, both nonTg and 3xTgAD mice exhibited greater individual variability in bioenergetic parameters suggestive of divergent bioenergetic phenotypes. Following transition through reproductive senescence, enzymes required for long-chain fatty acid (HADHA) and ketone body (SCOT) metabolism were significantly increased and variability in cytochrome c oxidase (Complex IV) collapsed to cluster at a ~40% decline in both the nonTg and 3xTgAD brain which was indicative of alternative fuel generation with concomitant decline in ATP generation. Conclusions These data indicate that reproductive senescence in the normal nonTg female brain parallels the shift to ketogenic/fatty acid substrate phenotype with concomitant decline in mitochondrial function and exacerbation of bioenergetic deficits in the 3xTgAD brain. General Significance These findings provide a plausible mechanism for increased life-time risk of AD in postmenopausal women and suggest an optimal window of opportunity to prevent or delay decline in bioenergetics during reproductive senescence.

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Section: Discussionsupporting

confidence: 91%

Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence

Yao

Hamilton

Cadenas

et al. 2010

Biochimica et Biophysica Acta (BBA) - General Subjects

136

140

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“…PDH is the key enzyme linking glycolysis to oxidative phosphorylation (OXPHOS); Complex I controls the entry of electron flow to the mitochondrial electron transport chain (mETC), hence controlling the entry point of OXPHOS in brain; Complex IV is the terminal enzyme of electron flow and reduces O 2 to H 2 O. Activity of PDH and COX is significantly decreased in postmortem Alzheimer’s brain tissue (Blass, et al, 2000, Martins and Hallmayer, 2004) whereas Complex I activity is compromised in Parkinson’s disease (Beal, 2005). In nonTg female mice, OVX induced a significant decline in PDH activity, while E2 treatment prevented the OVX-induced decline and sustained PDH activity to a level comparable to the Sham-OVX group (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid

Yao

Irwin

Chen

et al. 2012

Neurobiology of Aging

107

113

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Previously, we demonstrated that reproductive senescence was associated with mitochondrial deficits comparable to those of female triple-transgenic Alzheimer’s mice (3xTgAD). Herein, we investigated the impact of chronic ovarian hormone deprivation and 17β-estradiol (E2) replacement on mitochondrial function in non-transgenic (nonTg) and 3xTgAD female mouse brain. Depletion of ovarian hormones by ovariectomy (OVX) in nonTg mice significantly decreased brain bioenergetics, and induced mitochondrial dysfunction and oxidative stress. In 3xTgAD mice, OVX significantly exacerbated mitochondrial dysfunction and induced mitochondrial β-amyloid and Aβ−binding-alcohol-dehydrogenase (ABAD) expression. Treatment with E2 at OVX, prevented OVX-induced mitochondrial deficits, sustained mitochondrial bioenergetic function, decreased oxidative stress, and prevented mitochondrial β-amyloid and ABAD accumulation. In vitro, E2 increased maximal mitochondrial respiration in neurons and basal and maximal respiration in glia. Collectively, these data demonstrate that ovarian hormone loss induced a mitochondrial phenotype comparable to a transgenic female model of AD, which was prevented by E2. These findings provide a plausible mechanism for increased risk of AD in premenopausally oophorectomized women while also suggesting a therapeutic strategy for prevention.

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“…For some other complex disease such as familial breast cancer and Alzheimer’s disease, the early-onset cases might have strong genetic component [18], [19]. In other words, carriers of high-risk alleles are more likely to have an early-onset disease as compared with non-carriers.…”

Section: Discussionmentioning

confidence: 99%

Familial Correlations of Onset Age of Hepatocellular Carcinoma: A Population-Based Case-Control Family Study

Liu

Zhou

et al. 2014

PLoS ONE

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BackgroundThere was lack of evidence for familial aggregation in onset age of hepatocellular carcinoma (HCC) in Chinese population. We conducted a population-based case-control family study to examine familial correlation of age of HCC onset in Taixing, China.MethodsA total of 202 cases and 202 matched controls as well as their relatives were included in the study. Lifetime cumulative risks of HCC were estimated using the Kaplan-Meier approach. Cross ratios (CRs) were obtained from stratified Cox proportional hazard models, to assess the familial correlation of onset age.ResultsThe mean age of HCC onset was decreased as increasing number of HCC cases in a family. The onset age was the earliest for first-degree relatives, intermediate for second-degree relatives, and latest for non-blood relatives (spouse) (log-rank test, P<0.01). The onset age was significantly correlated between probands and their relatives. In stratified Cox proportional hazard models, the CRs for the probands versus their fathers, mothers, siblings and uncles/aunts were 6.25 (95% confidence interval (CI): 1.84–21.25), 9.81 (95% CI: 1.24–77.56), 6.22 (95% CI: 1.37–28.36) and 3.24 (95% CI: 1.26–8.33), respectively. After adjustment for hepatitis B virus infection, the CRs remained significant.ConclusionThis current study suggested a significant correlation of onset age for HCC among blood relatives. Familial HCC cases yielded earlier age of onset and their relatives have higher HCC risk in early age, highlighting intensive surveillance should be start at an earlier age for individuals with family history of HCC.

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Age at onset: important marker of genetic heterogeneity in Alzheimer's disease

Cited by 8 publications

References 9 publications

Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence

Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence

Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid

Familial Correlations of Onset Age of Hepatocellular Carcinoma: A Population-Based Case-Control Family Study

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