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The Alzheimer's disease mitochondrial cascade hypothesis
Serenoa
Posted: Wednesday, July 2, 2014 10:15 AM
Joined: 4/24/2012
Posts: 484


 

 Abstract

We first proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD) in 2004. Our core assumptions were a person's genes determine baseline mitochondrial function and durability, this durability determines how mitochondria change with advancing age, and critical changes in mitochondrial function initiate other pathologies characteristic of AD. Since then several lines of investigation report data consistent with or supportive of our hypothesis. In particular, AD endophenotype studies suggest a strong maternal genetic contribution, and links between mitochondrial function, tau phosphorylation, and amyloid-beta (Abeta) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce Abeta thus far have had at best very limited clinical benefits; our hypothesis identifies alternative therapeutic targets. While placing mitochondria at the apex of an AD cascade certainly remains controversial, it is increasingly accepted by the AD research community that mitochondria play an important role in the late-onset forms of the disease. Even if the mitochondrial cascade hypothesis proves incorrect, considering its assumptions could potentially advance our understanding of sporadic, late-onset AD.

 

 

http://www.ncbi.nlm.nih.gov/pubmed/20442494

 

 

I would like to re-examine this Mitochondrial Cascade Hypotheses.


Serenoa
Posted: Wednesday, July 2, 2014 2:11 PM
Joined: 4/24/2012
Posts: 484


This is super interesting. A very plausible hypothesis of how certain APP molecules could impact mitochondrial functioning.

 

From Journal of Neuroscience, 2006

 Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction

 
Discussion
Alzheimer’s disease is characterized by a
number of chronic injuries that eventually
cause progressive neurodegeneration. Mi-
tochondrial dysfunction is one of the ear-
liest defects that has been detected in AD
patients (Valla et al., 2001; Manczak et al.,
2004; Beal, 2005). In the present study, we
showtheaccumulationofnonglycosylated
APP species in mitochondrial import
channels of AD brain, which is directly as-
sociated with the impairment of mito-
chondrial functions as judged by the de-
crease in cytochrome c oxidase activity,
decreased capacity to re-duce MTT dye), and the in-
creased production of  H2O2.
This type of translocational arrest has been
observed for the first time in a disease con-
dition in situ in the human brain.
 
http://www.jneurosci.org/content/26/35/9057.full.pdf
 
 
  

Serenoa
Posted: Wednesday, July 2, 2014 3:50 PM
Joined: 4/24/2012
Posts: 484


This is a 2012 article from some of the same authors as the above research. This addresses the insulin connection to APP, beta-amyloid and fits with the mitochondrial cascade described above.

 

 

Mechanisms Underlying Insulin Deficiency-Induced Acceleration of β-Amyloidosis in a Mouse Model of Alzheimer's Disease

 

 

In conclusion, the results presented here demonstrate that STZ-induced insulin-deficient diabetes exacerbates Aβ accumulation by elevating expression levels of the β-secretase enzyme BACE1 and its substrate APP in the 5XFAD mouse model of AD. BACE1 elevations in diabetic 5XFAD mouse brains seem to be associated with translational upregulation through the PERK-eIF2α phosphorylation pathway rather than transcriptional mechanisms or changes in the GGA3-dependent lysosomal degradation. Our data support the hypothesis that deficient insulin signaling may represent a critical contributing factor in the acceleration of β-amyloidogenesis during the progression of sporadic AD and thus may be an important therapeutic target in AD treatments.

 

 

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032792

 


Serenoa
Posted: Wednesday, July 2, 2014 9:48 PM
Joined: 4/24/2012
Posts: 484


This is a really good discussion involving perspectives from several researchers.

 

 

Debating Insulin's Role in Alzheimer's

 In a recent symposium   at the New York Academy of Science, speakers agreed on the link between insulin resistance and Alzheimer’s, but beyond that, consensus was elusive. Is AD essentially “diabetes of the brain,” in which glucose utilization is impaired—or is it more a question of   insulin signaling processes  not directly related to energy management? - See more at: http://dana.org/News/Details.aspx?id=43285#sthash.TRzmlkor.dpuf

 

 http://dana.org/News/Details.aspx?id=43285

 

Debating Insulin’s Role in Alzheimer’s

 

Debating Insulin’s Role in Alzheimer’s
Debating Insulin’s Role in Alzheimer’s
Debating Insulin’s Role in Alzheimer’s

Serenoa
Posted: Saturday, July 5, 2014 8:15 AM
Joined: 4/24/2012
Posts: 484


Mitochonria are passed down maternally because these organelles come from the mother as part of the egg and reproduce on their own. They do not derive from a persons nuclear DNA. They are separate, and therefore, if there is a defect in the mitochondria causing AD, then we might expect to see AD being passed down maternally more often than by the father. However, this is not the case. So, if something is going wrong with mitochondria (mitochondrial cascade hypothesis, metabolic syndrome, etc.) then it happens later and is not a product of mitochondial inheritance. I think this is an important clue.

 

Maternal Transmission of Alzheimer Disease

 Abstract

Some propose maternal Alzheimer disease (1) inheritance. We compared dementia family histories in AD cases and cognitively normal controls. We expected more mothers to have AD in both groups. If maternal risk was not only due to female longevity more AD cases’ than controls’ mothers should be demented. We matched 196 AD cases to 200 controls by gender and age. We obtained parent dementia status and age of death for 348 AD and 319 control parents. 24 (12%) controls’ fathers, 26 (13%) AD patient fathers, 58 (29%) controls’ mothers and 55 (28%) AD mothers had memory difficulty. More mothers than fathers had memory problems in both groups and the statistical significance persisted after adjusting for parent age at death and APOE for controls (OR=2.40, p=0.004) but not cases (OR=1.63, p=0.14), although results are qualitatively similar. There was no evidence of a real difference between the two groups in interaction analysis (p=0.41). Mothers of both cases and controls were more often affected than fathers, even after adjusting for age. Cases’ mothers were no more often demented than controls’ mothers, which does not support the maternal AD transmission. Rather, the increased number of affected mothers relates, at least in part, to female longevity.

 


Serenoa
Posted: Tuesday, July 8, 2014 8:39 AM
Joined: 4/24/2012
Posts: 484


In a search for factors affecting mitochonria I have seen much evidence for the harmful role of increased homocysteine. High homocysteine levels are associated with Alz, and adversely affect mitochondral functioning.

 

"The observations that (i) homocysteine and H2O2, but not H2O2alone, caused a decrease in mitochondrial RNA levels, (ii) intracellular levels of H2O2 were significantly increased in the presence of homocysteine and Cu2+, and (iii) catalase, but not free radical scavengers, prevented a decrease in mitochondrial RNA levels, provide evidence that homocysteine and H2O2 act synergistically to cause mitochondrial damage. Furthermore, our findings suggest that intracellular glutathione and heat shock proteins play a role in protecting mitochondria against the adverse effects elicited by homocysteine and H2O2."

 

http://www.jbc.org/content/273/46/30808.short

 

Homocysteine levels are also associated with vitamin B deficiency with is a know cause of dementia.

 

Now, what I don't understand is that Down Syndrome individuals (who all get Alz pathology by age 50) have decreased homocysteine levels associated with overproduction of an enzyme on the 21st chromosome. I was expecting to find similar pathology between DS and Alz. Not the case in this instance, however, folate seem to help in both conditions/diseases.

 

"The results indicated that plasma levels of homocysteine, methionine, S-adenosylhomocysteine, and S-adenosylmethionine were all significantly decreased in children with DS and that their lymphocyte DNA was hypermethylated relative to that in normal siblings. The decreased availability of homocysteine promotes the well-established “folate trap,” creating a functional folate deficiency that may contribute to the metabolic pathology of this complex genetic disorder."

 

http://www.cell.com/ajhg/abstract/S0002-9297%2807%2961448-7

  


Lane Simonian
Posted: Tuesday, July 8, 2014 11:58 PM
Joined: 12/12/2011
Posts: 4863


This surprised me as well.  At first, I thought the low levels of homocysteine in people with Down Syndrome might lead to a less severe form of Alzheimer's disease, but this apparently is not the case.

 

The cleaving of the amyloid precursor protein increases hydrogen peroxide levels and maintain peroxynitrite levels, whereas amyloid plaques decrease hydrogen peroxide levels without stopping the production of peroxynitrites.  This is likely why amyloid oligomers are toxic, but are not sufficient to kill neurons, whereas Alzheimer's disease progresses even in the presence of plaques.   

 

Homocysteine is one of several factors that increase peroxynitrite levels.

 

http://ajprenal.physiology.org/content/ajprenal/279/4/F671.full.pdf


Serenoa
Posted: Wednesday, July 9, 2014 12:21 PM
Joined: 4/24/2012
Posts: 484


I have a tendency to passover simple solutions in favor of more obscure answers. With that in mind I've been looking at the role of vitamin B in Alz. Yes, there is an association. No, B12 supplements won't cure Alz. However, this vitamin B deficiency may offer us a clue to finding what will. It is associated with homosystiene which is tied to mitochondria and insulin, so I'm still on topic with this post.

 

 

VITAMIN B12 DEFICIENCY

 

"Many epidemiological investigations find an association between lower levels of B12 or folate (or elevated blood homocysteine and methylmalonic acid, which are indicators of folate or B12 deficiency) and Alzheimer disease or other forms of cognitive impairment (Clarke 1998; Wang 2001; Starr et al 2005; Kang et al 2006; Koike et al 2008; Kwok et al 2011). A community-based study of elderly persons similarly showed that serum indices of relative B12 levels were associated with increased risk of progressive brain atrophy over 5 years (Vogiatzoglou et al 200. Some studies in rodent models of Alzheimer disease demonstrate that both B-vitamin deficiency and hyperhomocysteinemia can increase levels of the amyloid forming peptides A-beta 1-40 and A-beta 1-42, increase levels of beta amyloid plaque, and cause cognitive impairment (Pacheco-Quinto et al 2006; Zhang et al 2009; Zhuo and Pratico 2010).

 

The discrepancy between the repeated finding of an association between indices of relative B12 deficiency and cognitive impairment and the lack of substantial benefit in therapeutic trials of B vitamin supplementation is not understood. The discovery that lower B12 levels are associated with a common allelic variant in the FUT2 gene (responsible for the so-called nonsecretor phenotype in the Lewis blood group system) suggests the possibility that the relationship between relatively low B12 levels and cognitive impairment is not necessarily causal in either direction, but that each could conceivably be related to a third inborn or acquired factor (Hazra et al 200."

 

http://www.medmerits.com/index.php/article/vitamin_b12_deficiency/P2


Serenoa
Posted: Thursday, July 10, 2014 9:51 AM
Joined: 4/24/2012
Posts: 484


Since mitochondrial dysfunction in Down Syndrome was found to contribute to the improper cleavage of APP by B-secretase (which leads to beta-amyloid), it is logical that mitochondrial dysfunction may be doing the same in AD brains. Since Leukine (gm-csf) has shown some benefits in treating AD, I asked the question does gm-csf improve mitochondrial function?Maybe that is how it is working. And, the answer is yes, it is possible.

 

Lane, this supports what you previously said about Luekine promoting the PI3k/Akt pathway.

  

 

GM-CSF provides autocrine protection for murine alveolar epithelial cells from oxidant-induced mitochondrial injury

 

 

 

“Hyperoxia induces cellular injury via effects on mitochondrial integrity, associated with induction of proapoptotic members of the Bcl-2 family. We hypothesized that GM-CSF protects AEC through effects on mitochondrial integrity. MLE-12 cells (a murine type II cell line) and primary murine type II AEC were subjected to oxidative stress by exposure to 80% oxygen and by exposure to H2O2. Exposure to H2O2 induced cytochrome c release and decreased mitochondrial reductase activity in MLE-12 cells. Incubation with GM-CSF significantly attenuated these effects. Protection induced by GM-CSF was associated with Akt activation.”

 

 

 http://ajplung.physiology.org/content/ajplung/302/3/L343.full.pdf

 

 

  


Serenoa
Posted: Thursday, July 10, 2014 11:47 AM
Joined: 4/24/2012
Posts: 484


This is important because other research has demonstrated that in Down Syndrome Bmi1 is inhibited. When Bmi1 is inhibited cells don't grow and regenerate. Over activation of Bmi1 can lead to cancer from too much growth. Keep in mind that Down's is very similar to AD, and that incidence of AD is lower in cancer patients (as I recall).

 

Bmi1 regulates mitochondrial function and the DNA damage response pathway

 

"Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1-/- phenotype. Here we demonstrate that cells derived from Bmi1-/- mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1-/- mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine "

 

http://www.nature.com/nature/journal/v459/n7245/full/nature08040.html