Introduction

Russell H. Swerdlow and Shaharyar Khan led this live discussion on 24 September 2004. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Live Discussion led by Russell H. Swerdlow and Shaharyar Khan on 24 September 2004.

Participants: J. Lowell; Mary Carmen Vazquez, Chile Pontifical Catholic University; Russ Swerdlow, University of Virginia; Shaharyar Khan, University of Virginia; Tom Fagan, Alzheimer Research Forum; Della David, University of Zurich; Jon Nilsen, University of Southern California; Rafal Smigrodzki, Gencia Corporation; Sam Birch; P. Hemachandra Reddy, Oregon Health Science; Keith Crutcher, University of Cincinnati, Ohio; Stacey Trotter, University of Virginia; Mike Leski, University of Nevada, Reno; Roberta Diaz Brinton, University of Southern California; Wycliffe Opii, University of Kentucky; Mark Pugh, Novartis Neuroscience; Zun-Ji Ke, Shanghai Institute for Biological Sciences.

Note: The transcript has been edited for clarity and accuracy. __________________________________________________________

Tom Fagan
Hi, everyone. I'm Tom Fagan and I will be moderating today.

Russ Swerdlow/Shaharyar Khan
Hi, Tom and Mary.

Tom Fagan
Hi, Della.

Della David
 Hello.

Tom Fagan
Okay, we have a few more who will be joining us, but I think we should get started. Russ, Shaharyar, do you want to just outline the salient points and then open it up to questions? Shoot...

Russ Swerdlow/Shaharyar Khan
First, thanks to Alzforum for this opportunity. Essentially, our hope is to develop a hypothesis that accounts for sporadic AD and ties together different histopathological observations. One important point is we believe that in sporadic AD, what are presumed to be pathophysiological events are happening for a reason.

Tom Fagan
Russ/Shaharyar, what needs to be done to prove your hypothesis? What are the next experimental steps?

Russ Swerdlow/Shaharyar Khan
First, continue sequencing of mtDNA in AD (currently ongoing by the groups of Davis Parker, Flint Beal, and Doug Wallace). Second, transfer mutated mtDNA in animal models (as Nils Goran Larrson is doing this). Third, reverse the AD phenotype by replacing damaged mtDNA.

Rafal Smigrodzki
Drs. Swerdlow and Khan, how do you explain the fact that all of the familial cases of AD result in increased Aβ? Also, do familial mitochondrial DNA (mtDNA) mutations yield an AD phenotype?

Russ Swerdlow/Shaharyar Khan
Particular mtDNA mutations are known to produce a neurodegenerative phenotype, indeed, at strikingly early ages. One published MELAS (MELAS=mitochondrial encephalopathy, lactic acidosis, and stroke) patient autopsy did reveal AD pathological changes. The fact that all familial cases of AD increase Aβ is not a problem with our hypothesis, but rather points out a nexus between the dominant and sporadic cases. The key question is: If mitochondrial dysfunction and Aβ both occur in AD, which comes first in the sporadic cases?

Hemachandra Reddy
Russell/Shaharyar, your article is great and I enjoyed reading it—particularly about sporadic AD and its connection with mitochondrial dysfunction. I agree with your mitochondrial theory. However, it is not clear how mitochondrial oxidative damage leads to cleavage of APP and β amyloid formation?

Russ Swerdlow/Shaharyar Khan
Hemachandra, thanks. At an enzymatic level, it's not quite clear how APP cleavage is altered. It is, nevertheless, observed in both models of toxin-induced complex IV inhibition, as well as in cytoplasmic hybrids (cybrids) expressing mtDNA from sporadic AD subjects. We believe APP cleavage to Aβ actually represents an attempt to downregulate excessive ROS (reactive oxygen species) produced by dysfunctional mitochondria. In our view, Aβ evolved with a physiologic purpose, perhaps to tune down ROS.

Hemachandra Reddy
Russ/Shaharyar, You mean reduce ROS and compensate ATP levels.

Russ Swerdlow/Shaharyar Khan
Yes, reduce ROS and upregulate a glycolytic contribution to ATP production, which in itself likely affects nuclear gene expression (hypoxic gene expression).

Tom Fagan
So what fraction of the mitochondria proteins are encoded in the mitochondria versus the nucleus, and should we be looking at nuclear-encoded mitochondrial genes, too?

Russ Swerdlow/Shaharyar Khan
Only a small percentage of mitochondrial proteins are mtDNA encoded (13 of ~1000). Looking at nuclear gene expression will also prove informative; Hemachandra had a wonderful paper a few months ago showing mitochondria-relevant nuclear gene changes occurred relatively early in APP mice.

Hemachandra Reddy
Russell/Shaharyar, yes, I agree; both mitochondria and nuclear genes are important.

Mary Carmen Vazquez
How does Aβ reduce ROS? What about the idea of oxidative stress as a toxic mechanism for Aβ itself?

Russ Swerdlow/Shaharyar Khan
β-sheet proteins can cause membrane permeabilization; doing so to the mitochondrial membrane would essentially uncouple electron transport, and at physiologic levels shut off effective mitochondrial proton pumping and ROS. Also, see a recent paper from Smith and Perry's group (Nunomura et al., 2004) showing that where Aβ exists, there is actually less evidence of oxidative stress in familial Alzheimer disease (FAD) and transgenic (Tg) models.

Hemachandra Reddy
Russell/Shaharyar, in sporadic AD, which one comes first, mitochondrial dysfunction or APP derivatives, soluble or insoluble β amyloid?

Russ Swerdlow/Shaharyar Khan
We believe the mitochondrial dysfunction—our cybrid data certainly suggest mitochondrial dysfunction is sufficient to change APP catabolism to Aβ1-40 and 1-42.

Rafal Smigrodzki
I think the insulin/diabetes link is very compelling in AD. How does mitochondrial dysfunction play out there?

Russ Swerdlow/Shaharyar Khan
We would argue the relationship suggests a common underlying pathophysiology; primary mitochondrial dysfunction would make a plausible candidate.

Hemachandra Reddy
Russ/Shaharyar, what is the precise connection between mitochondrial dysfunction and APP cleavage? I mean, how does mitochondrial dysfunction cause β oligomers.

Russ Swerdlow/Shaharyar Khan
The data are insufficient in some respects. We would guess somehow that mitochondrial dysfunction or oxidative stress shifts APP processing to amyloidogenic derivatives that are suited to form oligomers. This could be initiated by altered calcium handling or caspase activation (or any of the biological sequalae of increased ROS/bioenergetic failure).

Jon Nilsen
Dr. Swerdlow and Dr. Khan, your hypothesis states that neuronal progenitors attempt to enter the cell cycle, resulting in aneuploidy. What does your model predict to be the outcome of therapeutic treatments designed to promote stem cell division?

Russ Swerdlow/Shaharyar Khan
In terms of promoting stem cell division, we are rather skeptical. First, it would not address the underlying primary pathology (stem cells acquire mtDNA mutations, as well). Further, it already appears that endogenous attempts in which stem cells try to adapt AD brains to the underlying pathology are ineffective.

J. Lowell
Dear Drs., are you familiar with the article by Mattson et al. on modification of brain aging by genes, diet and behavior?

Mary Carmen Vazquez
Drs. Swerdlow/Khan, about altered calcium homeostasis and caspases: What would be the role of the endoplasmic reticulum?

Della David
Concerning Aβ reducing ROS: Considering its action on the ETC (electron transport chain) complex IV, would it not be more logical, and in keeping with the pathology of AD, that this would create more ROS? In a recent paper from Palacino et al., 2004 on parkin-deficient mice, they showed reduced proteomic levels of Complex I and IV with also reduced respiration rates and demonstrated on the other hand increased ROS damage in the mice.

Hemachandra Reddy
Russ /Shaharyar, it is possible that increased ROS may activate β- and γ-secretases and initiate APP cleavage to β amyloid. I have not yet seen a publication to support this; I may be wrong.

Russ Swerdlow/Shaharyar Khan
I think what needs to be considered is the underlying state of the mitochondria. Are they functional or not to begin with? Altering healthy mitochondria may reveal different consequences than altering sick ones. This might help explain why APP transgenic mice show very little degeneration. We agree with Mattson on the contribution of diet, redox genes, and lifestyle on the aging phenotype. We don't necessarily think stem cells are the answer. We do believe the brain is attempting to replace lost neurons, however.

Roberta Diaz Brinton
Dear Drs., can you elaborate on the stem cell adaptation or lack thereof in AD? Herrup's group found that cell cycle gene expression predicted cell death. Is this what you are referring to as the adaptation? It would be expected that stem cells would be just as vulnerable to AD pathology, but is there evidence for this?

Russ Swerdlow/Shaharyar Khan
We think that stem cells are receiving a signal to reenter the cell cycle, but are not very good at it. To clarify one point, however, the Herrup paper was documenting aneuploidy in neurons, not necessarily stem cells. In that regard, it is maladaptive; neurons that attempt to reenter the cell cycle will fail. But this issue of cell cycle reentry is critical; why is it happening? We think as cells go anaerobic, a dedifferentiation response is initiated.

Tom Fagan
Russ/Shaharyar, do you mean "go anaerobic" because the respiratory chain becomes inefficient, or in a response to Aβ oligomers?

Russ Swerdlow/Shaharyar Khan
A key point. Intrinsic mitochondrial dysfunction and β amyloid-induced secondary mitochondrial dysfunction likely play a role. Increased ROS from an inefficient ETC causes an increase in Aβ levels, which in turn was probably intended to downregulate mitochondria function, causing a compensatory increase in glycolysis. Also, mitochondrial failure simulates a hypoxic state, and stimulates an appropriate hypoxia response.

Mike Leski
Drs. Swerdlow/Khan, sick versus healthy mitochondria is an important point. Transgenics, in my mind, favor the Aβ story, but as you point out, don't tell us much about the early state of the disease.

Russ Swerdlow/Shaharyar Khan
The transgenic mice are probably usable models for people with APP mutations, but don't address issues of etiology in sporadic AD.

Roberta Diaz Brinton
Dear Drs. Swerdlow and Khan and Alzforum, before our time ends, many thanks for taking the time to chat—most informative—as is your recent publication on the mitochondrial cascade and AD. Much appreciated! Robbie.

Hemachandra
Russ/Shaharyar, I agree; APP transgenic mice support the β amyloid theory. In late-onset sporadic AD, the situation is different.

Mary Carmen Vazquez
Drs. Swerdlow/Khan: If mitochondrial dysfunction triggers Aβ oligomer overproduction, what causes mitochondria dysfunction in "sporadic" cases: aging? Maternal mitochondria DNA mutations aren't a kind of inheritance?

Russ Swerdlow/Shaharyar Khan
Mary, thank you for bringing this up. We believe mitochondrial dysfunction arises intrinsically, in the mitochondria, from mtDNA. We predict (and data support) that somatic mtDNA mutation may contribute. However, we further feel that rates at which mtDNA mutation are acquired are determined by the inherited gene-determined efficiency of one's electron transport chain.

Hemachandra
Mary, I think aging. We have a paper coming in J Neurochemistry to explain mitochondria dysfunction and aging in mice.

Tom Fagan
Russ/Shaharyar, what about the gene-determined efficiency? Are there known polymorphisms that give one a "super" ETC?

Russ Swerdlow/Shaharyar Khan
It has been shown that particular mtDNA haplogroups influence Parkinson and Alzheimer risk, and affect aging success in general.

Hemachandra
Russ/Shaharyar, I enjoyed this chat. Thanks to ARF and you both for a nice chat.

Russ Swerdlow/Shaharyar Khan
Hemachandra, can you tell us about your paper?

Mary Carmen Vazquez
Hemachandra, thanks. I'll read your paper

Hemachandra
We looked at time course (two months, 12 months, 18 months, and 24 months), mitochondrial gene expression, oxidative damage, and cytochrome c release, and we found mitochondrial gene expression is upregulated in 12 months and then gradually decreased in 18 and 24 months relative to two-month-old mice. In 24-month-old animals, there is hardly any compensation to reduce ROS. We can talk further, or if you need the full paper, I can send it to you soon.

Russ Swerdlow/Shaharyar Khan
Hemachandra, our interpretation of those data is that Aβ is inhibiting healthy mitochondria, which initially try to compensate by upregulating to maintain function. Eventually, the compensation curve is exceeded as ROS generation continues. Please send the paper.

Rafal Smigordzkil
Drs. Swerdlow/Khan, by your account, if we live long enough, we all have AD to look forward to!

Russ Swerdlow/Shaharyar Khan
Rafal, we are all on a trajectory of neurodegeneration that may cause AD. Some with very slow trajectories might need to survive into extreme ages; some with more rapid trajectories will get into trouble at earlier ages. Other genetic factors, such as ApoE genotypes, likely influence this trajectory. Also, in older age groups, AD is extremely common...in this case, is it really a disease that is separate from aging itself?

Tom Fagan
Eukaryotes are a victim of their own success; they stole those mitochondria and now we're paying for it!

Russ Swerdlow/Shaharyar Khan
It's not a one-way street; by incorporating into eukaryotic cells, mitochondria also benefited. Eukaryotic cells probably offered protection from bacterial phages!

Rafal Smigordzkil
The dedifferentiation phenomenon is very interesting. What you are postulating is an increase in hypoxic signaling in response to mitochondrial dysfunction and Aβ production that induces a dedifferentiation response (much like the Warburg hypothesis of cancer).

Russ Swerdlow/Shaharyar Khan
Rafal, you are absolutely right. It would be intriguing to understand why neurons fail in adapting to mitochondrial dysfunction; why do they get arrested in G2-M cell cycle transition in AD, as Herrup and others have shown?

J. Lowell
Dear Drs., there has been nothing stated as to mitochondria and electron transport in other tissues on aging? Comparison?

Russ Swerdlow/Shaharyar Khan
ETC activity in multiple tissues is reduced in both aging and AD.

Tom Fagan
Russ/Shaharyar, are there parallels in other aging tissues? Is Aβ, or a different β-sheet oligomer, produced in muscle, for example, which must have a lot of mitochondria. What makes neurons different?

Mary Carmen Vazquez
Drs. Swerdlow/Khan, mitochondria dysfunction would play a role in inclusion body myositis?

Rafal Smigordzkil
You have failed to mention tau; what role do mitochondria play in tangle formation?

Russ Swerdlow/Shaharyar Khan
In our paradigm, with bad mitochondria, cells going anaerobic, and trying to dedifferentiate, there is no longer an advantage to transporting mitochondria down an axon (a feature of differentiated cells). Tau phosphorylation will turn off organelle transport down axons (APP may have a role in this, as well). Also, tau phosphorylation is seen in fetal states, when cells are dividing and microtubules are mitotic spindles rather than cytoskeletons.

J. Lowell
Dear Drs., that is known clinically probably. But mitochondria and brain and other tissues? Does it always follow that decreasing ECF leads to mitochondrial dysfunction and to dementia (brain) (and in other tissues)?

Russ Swerdlow/Shaharyar Khan
Good points; mitochondria dysfunction in highly differentiated tissue such as brain, muscle, and pancreas may drive amyloid-like (β-sheet) protein production, which may have evolved for a reason. Inclusion body myositis (IBD) and perhaps type II diabetes are great examples.

Della David
Has there been pathology linked to the reduced ETC in peripheral tissues in AD? Considering the very negative consequences of platelet mtDNA in cybrids, wouldn't one expect something quite significant in peripheral tissues as well as in the brain?

Tom Fagan
All, before we go our separate ways, I'd like to thank Russ and Shaharyar for taking this on. It is certainly fascinating. Mitochondria seem to be where it is at these days. You all may want to take a look at our recent coverage of a paper by Charlie Glabe, who just showed that Aβ oligomers permeabilize lipid bilayers leading to dramatic increases in conductance without affecting any specific ion channel (see ARF related news story). Seems to fit nicely with today's topic.

Russ Swerdlow/Shaharyar Khan
J. Lowell, tissue vulnerability to mitochondrial dysfunction would be directly correlated with the particular tissues' reliance on oxidative metabolism (as opposed to other energy sources). Phenotype changes outside of brain include COX negative fibers, loss of subcutaneous fat, perhaps glucose intolerance. Thank you, everyone; if there are any further questions, please feel free to e-mail us.

Tom Fagan
Thanks, all, for your participation. I will send you the edited transcript for review soon.

Mary Carmen Vazquez
Thanks for the chat. It was a great challenge for me.

Mike Leski
Nice chat. Before I leave, I'll note that an interesting recent paper in PNAS demonstrated that inactive individuals are more likely to get AD than active ones. Mitochondria are damaged during intense neuronal activity, but also are repaired during this process. I have some tantalizing results that APP directs this process. Thus, it may be possible that sporadic and familial forms of the disease have a common base.

Russ Swerdlow/Shaharyar Khan
Thanks Tom. Mike, e-mail us to tell us more about your work.... That's cool!

Tom Fagan
Mike, have you published or are you about to publish that?

Mike Leski
No. It's a work in progress that I'd like to discuss with others.

Russ Swerdlow/Shaharyar Khan
Mike, keep at it, and if you don't mind, we'd love to hear more about your work.

Mark Pugh
Very interesting information to consider. I would like to review the edited transcript.

J. Lowell
Dear Drs., thanks.

 

Background

Background Text

The amyloid cascade hypothesis has been evoked to explain the pathology that underlies Alzheimer disease. It claims that "deposition of Aβ, the main component of plaques, is the causative agent of Alzheimer's pathology, and that the neurofibrillary tangles, cell loss, vascular damage, and dementia follow as a direct result of this deposition" (see Hardy et al., 1992).

But what triggers deposition of Aβ—what lies upstream? Recently, in the journal Medical Hypotheses, Russell Swerdlow and Shaharyar Khan proposed the "mitochondrial cascade hypothesis," which attempts to tie together seemingly disparate pathological features of the disease. Read the full hypothesis then join us on Friday, 24 September 2004, when Russell and Shaharyar lead a Live Discussion on their theories. We are grateful to Elsevier Ltd. for providing Alzforum with the manuscript free of charge.—Tom Fagan

See Full Text (.pdf) of this article.

Reprinted from with permission from Elsevier. Swerdlow, Russell H. and Khan, Shaharyar. A "Mitochondrial Cascade Hypothesis" for Sporadic Alzheimer's Disease. Medical Hypotheses. 2004; 63: 8-20. See ScienceDirect.

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References

Webinar Citations

  1. A "Mitochondrial Cascade Hypothesis" for Sporadic Alzheimer's Disease

News Citations

  1. Protofibrils Permeabilize Lipid Membranes

Paper Citations

  1. . Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992 Apr 10;256(5054):184-5. PubMed.
  2. . Neuronal RNA oxidation is a prominent feature of familial Alzheimer's disease. Neurobiol Dis. 2004 Oct;17(1):108-13. PubMed.
  3. . Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiol Rev. 2002 Jul;82(3):637-72. PubMed.
  4. . Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004 Apr 30;279(18):18614-22. PubMed.

Other Citations

  1. See Full Text (.pdf) of this article

External Citations

  1. ScienceDirect

Further Reading

Papers

  1. . Cholinergic switching within neocortical inhibitory networks. Science. 1998 Aug 14;281(5379):985-8. PubMed.