Analysis of European mitochondrial haplogroups with Alzheimer disease risk

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Stavia
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Postby Stavia » Wed Mar 04, 2015 6:09 pm

Omg. I just thought of something. Mitochondrial DNA is completely different to cellular DNA right? So how can apoe4 affect mitochondrial function?

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Julie G
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Re: Analysis of European mitochondrial haplogroups with Alzheimer disease risk

Postby Julie G » Wed Mar 04, 2015 6:57 pm

Dr. Huang/Gladstone tackles the topic below in a nice synopsis. You can chase down his references; Reiman & Caselli's work, plus a few others.
http://labs.gladstone.ucsf.edu/huang/pa ... e-research

ApoE4 and its fragments impair mitochondrial function
Mitochondrial dysfunction has been reported in AD, which is modulated by apoE genotype, with a greater effect in apoE4 than in apoE3 carriers [121-124,125]. In both AD patients and age-matched nondemented subjects, apoE4 is associated with decreased cerebral glucose metabolism [126-135], an effect that occurs decades before cognitive impairment become apparent [126,127,136] and, probably, also before significant Aβ deposition. Thus, apoE4 may cause mitochondrial dysfunction at very early stages in life. Mitochondrial dysfunction is clearly coupled with production of reactive oxygen species and increased oxidative damage, which in turn further impair mitochondrial activity. Temporary or sustained loss of mitochondrial function impairs cellular defenses and repair mechanisms, decreasing the ability of neurons to mount an appropriate stress response and causing cellular injury.

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Stavia
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Re: Analysis of European mitochondrial haplogroups with Alzheimer disease risk

Postby Stavia » Wed Mar 04, 2015 11:05 pm

Yes I know this, but HOW can this be one size fits all if mitochondrial DNA is a separate pool. There has to be other mitochondrial genes present to be interacting variably badly with the apoe4 which would account for us reacting differently. For instance Julie and I are on completely different poles glucose metabolism wise. My mitochondrial DNA is m33c. Its from Belarus. Dunno yours Julie. Perhaps we are significantly different mitochondrial-interaction-with-apoe4-wise too. The mitochondrial metabolism study on the young apoe4s was a very small sample.

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Julie G
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Re: Analysis of European mitochondrial haplogroups with Alzheimer disease risk

Postby Julie G » Thu Mar 05, 2015 6:52 am

Stavia, this is way over my head...distinguishing between mitochondrial DNA and cellular DNA :? I'll have to work to better understand it. The idea that some haplogroups may have protection from the mitochondrial deficiency that accompanies E4 is interesting.

The mitochondrial metabolism study on the young apoe4s was a very small sample.


My understanding of Reiman and Caselli's work is that it spans almost 20 years with a data set between 150-200. The participants are cognitively normal, between the ages of 47-68 y/o, many are E4 homozygotes. They underwent PET- FDG scans, and other extensive testing, every two years. Reiman & Caselli have consistently found/reported that E4 carriers demonstrate reduced/impaired cerebral glucose metabolism in the same brain regions as AD patients. They may have ALSO looked at some younger (smaller group) of E4s and found the same phenomenon that adds to the breadth of this discovery. I would be hesitant to dismiss this report due to small sample size.

We are currently recruiting for this study:
viewtopic.php?f=15&t=1200

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Stavia
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Postby Stavia » Thu Mar 05, 2015 10:32 am

Julie, the entirety of the mitochondrial DNA is inherited from the mother's egg cytoplasm. It is completely separate from the nuclear DNA and remains so thru every generation. Every mitochondria in our cells results from division of the first bunch in that egg. Functionality of the mitochondria is a result of the mitochondrial DNA......or do nuclear DNA products ie proteins VARIABLY interact with the mitochondrial functions depending on the mitochondrial subtype?
Im absolutely not saying there's not a mitochondrial issue in e4s. There obviously is. Im saying the sample size was too small to see what variation in the mitochondrial DNA made to the defective glucose metabolism.

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Re: Analysis of European mitochondrial haplogroups with Alzheimer disease risk

Postby SusanJ » Thu Mar 05, 2015 2:09 pm

Reading further down in the Gladstone page, they mention:

Biophysical studies suggest that the lipid-binding domain within the C-terminal-truncated apoE4 has a less organized structure and greater exposure of the hydrophobic residues than full-length apoE4 [142,143], which might increase the interaction with mitochondrial membrane. Interestingly, almost 20 years ago, it was found that apoE avidly bound to mitochondrial ATPase [144]. In addition, small amounts of apoE have been identified in hepatocyte mitochondria [145]. Blocking the interaction of apoE4 fragments with mitochondria might prevent the detrimental effects on mitochondria function, and increasing the activity or number of mitochondria in neurons might also eliminate the detrimental effect of apoE4 fragments (Figure 2).


So, the connection might be the impacts of apoE4 fragments on ATPase?

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Stavia
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Postby Stavia » Thu Mar 05, 2015 7:35 pm

Clever girl Susan! The mitochondrial membrane would be consistent across mitochondrial genotypes one would think

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Re: Analysis of European mitochondrial haplogroups with Alzheimer disease risk

Postby LillyBritches » Thu Mar 05, 2015 7:43 pm

Don't have time to read in-depth, but the only maternal (mitochondrial) haplogroups I've ever come across as being over-represented in, and a risk for, AD are H5 (sub-haplogroup) and U (U is under-represented in AD females but over-represented in AD males):

http://www.plosone.org/article/fetchObj ... tation=PDF

The above is from 2010 and the paper Edward referenced is from 2004.
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Re: Analysis of European mitochondrial haplogroups with Alzheimer disease risk

Postby asiagillett » Fri Mar 06, 2015 6:25 am

Yeah guess what mine is???? H5!! Awesome. I just can't seem to escape bad news. I purposely avoid snp's but still have a creeper pop up in my haplo group.

Oh well. Nothing I can do so just moving on.

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Re: Analysis of European mitochondrial haplogroups with Alzheimer disease risk

Postby circular » Fri Mar 06, 2015 7:40 am

"Functionality of the mitochondria is a result of the mitochondrial DNA......or do nuclear DNA products ie proteins VARIABLY interact with the mitochondrial functions depending on the mitochondrial subtype?" ... I forget who it was here who once wrote they felt the real answer to all this would be a molecule that changes the structure of E4. If they could solve that then it wouldn't stick all over the mitochondria.

My favorite thing about mitochondrial DNA is that it is BACTERIAL DNA from waaaaaaaay long ago! Julie this might help http://learn.genetics.utah.edu/content/ ... rganelles/
ApoE 3/4 > Thanks in advance for any responses made to my posts.


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