Paul Coleman, with Carl Cotman, Mark A. Smith, and George Perry, led this live discussion on 24 March 1999. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

View Transcript of Live Discussion — Posted 6 September 2006

Preliminary Questions for the Panel

What is the most compelling evidence that apoptosis does/doesn't play an important role in AD pathogenesis?

Mark Mattson: The strongest evidence is as follows:

1. "Patchy" distribution of degenerating neurons within an affected brain region. An important feature of apoptosis is that cells die "one-by-one" as opposed to necrosis where there is massive death of grouped cells.

2. Molecular, biochemical and immunohistological analyses of AD brain tissue reveal many "markers" of apoptotic cascades including caspase activation, increased Par-4 levels, changes in levels of Bcl-2 family members, and evidence for DNA damage.

3. Studies of cell culture and animal "models" of AD reveal that environmental (e.g Aβ and iron) and genetic (APP and presenilin mutations) aberrancies linked to AD can promote neuronal apoptosis.

4. Synapse loss and neuritic degeneration are prominent features of AD that are strongly correlated with cognitive dysfunction. As first reported by our group last year (Exp. Neurol. 153:35-48 and Brain Res. 807: 167-176), and recently confirmed by Carl's group, apoptotic cascades can be induced locally in synaptic terminals and neurites by insults relevant to AD pathogenesis (e.g., exposure to Aβ, glutamate and iron).

Mark Smith and George Perry: The most compelling evidence that the vast majority of vulnerable neurons are not undergoing apoptosis is that there are vulnerable neurons that all display apoptotic-like changes year after year. Simply, they are not dying. The conclusion that apoptosis is involved is based on culture studies where neurons are always living at the edge or mistaken concepts that apoptotic changes equal apoptosis. Perhaps this is a semantic issue but one might expect death in apoptosis!

Most studies on apoptosis rely on TUNEL/DNA fragmentation or "apoptotic" markers. DNA cleavage, whether by endlabeling or laddering, is not apoptosis-specific since oxidative damage and repair gives the same pattern. Also, what apoptotic markers are truly apoptotic-only? For the ones described in AD, most, if not all, could have arisen by alternate mechanisms.

How does one reconcile the apoptosis model with the fact that Alzheimer's appears to be a slow, chronic neurodegenerative process?

Mark Mattson: That AD is a slow, chronic neurodegenerative process strongly favors an apoptotic (versus necrotic) mode of neuronal death. Numerous studies (in cell culture and in vivo) have shown that lower intensity, longer duration insults will induce neuronal apoptosis, whereas higher intensity insults will induce necrosis. Examples include titration of exposure to glutamate, iron and Aβ in culture, and the gradient of neuronal injury in focal ischemia - necrosis in the ischemic core (region of intense ischemia) and apoptosis in the penumbra (region of milder ischemia).

How does one know whether or not the apoptosis one is seeing isn't something that occurred immediately before death?

Mark Mattson: Does neuronal apoptosis occurs immediately prior to death of the AD patient? This is a concern with any analysis of end-stage AD brain tissue. Thus, the same question could be posed to Mark Smith (does increased oxidative stress occur immediately prior to death?) and Paul Coleman (do changes in gene expression occur immediately prior to death?). Arguing against such a scenario is that apoptotic changes are not seen in age-matched controls, including disease controls which also suffer from end-stage agonal stress. Also arguing against this scenario are data from animal models (e.g., mice expressing AD-linked APP and presenilin mutations). Nevertheless, there is clearly a need for studies of biopsy tissue.

In AD, is apoptosis something that's happening to relatively healthy cells, or to cells that are already very sick and dysfunctional? If it's the latter, does it make sense to develop antiapoptotic agents as therapies?

Mark Mattson: I believe apoptotic cascades are activated quite early in synaptic terminals and contribute to both the early synaptic degeneration and ultimate cell death. Again, I refer you to our data (Mattson et al., Exp. Neurol. 153:35-48 and Mattson et al., Brain Res. 807: 167-176) (also manuscript in press in J. Neurochem. showing that Par-4 is induced in synaptic terminals by AD-relevant insults, wherein it promotes local mitochondrial dysfunction and caspase activation), Carl's recent findings, as well as Greg Cole's and Elizer Masliah's data from studies of postmortem brain tissue. Concerning therapies, it is my view that the best approach is prevention, and that efforts aimed at reducing oxidative stress such as calorie restriction (see our recent article by Bruce-Keller et al. Annals Neurol. 45: 8-15) and increased antioxidant intake, are currently the most rational approach. Nevertheless, efforts should continue to identify specific targets for therapeutic intervention.

Are Smith and Perry questioning whether apoptosis occurs at all in AD, or whether apoptosis plays an important role in neuronal death in AD?

Mark Smith and George Perry: Apoptosis is so important for a postmitotic neuron it can make no error and therefore the central issue in AD is how with all the oxidative damage and mitochondrial degeneration neurons still remain. Whether they finally die by apoptosis or other mechanisms is less important than the avoidance issue. We say this because what the neuron does to avoid death is probably leaving it functionless. The choice open to neurons is apoptotic death or a protracted state of avoiding it. In either case, the function of neurons is lost.

There appear to be a number of different paths to programmed cell death. Would you characterize the molecular pathways of some? Is one predominant in AD?

Mark Mattson: Concerning molecular pathways of programmed cell death - there are clearly some predominant components, as well as some cell-type and paradigm-specific components. Increased oxidative stress, Par-4 induction (Guo Q et al, Nature Med., 4: 957-962) and mitochondrial calcium overload are important early factors in the cell death process in most apoptotic paradigms. Important components of subsequent phases include caspase activation and the generation of "apoptotic factors" that lead to nuclear disintegration. Cell-type and paradigm-specific factors include various receptor-linked cascades (e.g., Fas, TNF, etc) and participation of certain Bcl-2 family members.

Mark Smith and George Perry: We think the paths of neuronal death in chronic conditions is only beginning to emerge but we note in some of the earliest studies of cell death, more than necrosis and apoptosis were offered as alternatives. At this point, the cell death of AD may be characterized as "delayed apoptosis", but more clear definitions are required.

Do these different pathways to cell death converge on a final common path? If so, what is this final common path?

Mark Mattson: There appear to be several essential links in the chain of events resulting in cell death. Oxidative stress, Par-4 induction, mitochondrial dysfunction and caspase activation are steps that are clearly essential for neuronal death in various experimental models because antioxidants, suppression of Par-4 production, agents that stabilize mitochondrial function and caspase inhibitors can prevent cell death. However, one clearly wants to interrupt the cell death process at an early stage because some manipulations that prevent neuronal death (e.g., caspase inhibitors) may not prevent neuronal dysfunction.

Mark Smith and George Perry: We really cannot venture as to whether all cell death pathways are the same. Apoptosis and necrosis are distinct. Apoptosis and what for want of a better term delayed apoptosis may in the final point be the same. Maybe exactly the same in terms of molecular changes only the key being timing. And that key is everything since it offers hope of intervention.

What may be some of the specific stimuli to programmed cell death in the Alzheimer's brain?

Mark Mattson: Stimuli for apoptosis in AD likely include increased levels of oxidative stress, perturbed calcium homeostasis, accumulation of aggregating Aβ, and reduced energy availability to cells. Each of these factors is known to be age-related, and studies of genetic models of AD (cells and mice expressing APP or presenilin mutations) support their involvement in the pathogenic process.

Mark Smith and George Perry: We think the major stimuli to an apoptotic pathway is mitochondrial degeneration with oxidative damage and mitochondria as the key. An alternate mechanism likely contributing to "apoptotic-like" changes is re-entry into the cell cycle.

Are the molecular pathways to cell death in the AD brain a recapitulation of the mechanisms used during early development to eliminate excess neurons?

Mark Mattson: There is no doubt in my mind that some of the same signaling mechanisms that regulate development of neuronal circuits (e.g., activation of glutamate receptors and neurotrophic factor signaling) are also involved in the pathogenesis of AD. I organized a Symposium at the 1990 Neuroscience meeting entitled "Recapitulation of Developmental Mechanisms in Neurodegenerative Disorders". Carl gave a talk in that Symposium, and even at that time it was clear to us that at least some aspects of the cell death process in AD were similar to those employed during development. Work in the subsequent 9 years has strongly supported the involvement of developmental signaling pathways in AD and other neurodegenerative disorders.

Mark Smith and George Perry: In development, neurons are lost rapidly and by an apoptotic mechanism. In AD, they are lost slowly.

Is NFT formation a necessary prelude to cell death in the AD brain?

Mark Mattson: Whether NFT formation is necessary for neuronal death in AD remains unclear. What seems clear, however, is that the biochemical alterations that cause NFT formation are associated with the cell death process. That tau mutations can promote neuronal death in Frontotemporal dementia strengthens the case for involvement of tau in the cell death process. However, the formation of NFT per se may be less important than dysfunction of the microtubule system.

Mark Smith and George Perry: NFT formation is not required for cell death. We, Terry, and later Hyman, demonstrated this for neurons. We think instead that NFT are an anti-apoptotic change. NFT are in neurons with problems but if not there, they would be worse. We found this clearly for oxidative damage.

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