Peter Nelson led this live discussion on 26 March 1998. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Paper Under Discussion: Neve RL and Robakis NK. Alzheimer's disease: a re-examination of the amyloid hypothesis. TINS. 21 (1);1998:15-19. Abstract

View Transcript of Live Discussion — Posted 6 September 2006

Background Text
By Peter Nelson

The debate at hand is whether the deposition of extracellular A-β peptide is an early and integral feature in the biochemical progression of Alzheimer's disease (AD). The purpose of this brief discussion is to concisely outline the review article's points questioning the data in support of a fundamental role of Aβ in AD; to describe some counter-arguments that Dr. Selkoe or others might use to justify a fundamental role of β in AD; and finally, to provide some editorial third- party perspectives on the issue.

Main points of the review article

1. The neurotoxicity of β has not been convincingly established.

i. Many different avenues of β neurotoxicity have been described, some overlapping, but others seemingly contradictory of each other. The article notes fourteen such hypothesized routes of β toxicity. There is confusion, rather than consensus, in this field.

"Pro β" response: Simply because β appears to be toxic in many ways is not a good argument that it is not toxic. Some of the hypotheses are perfectly compatible with each other. For example, were β to increase intracellular calcium, it would also be expected to induce oxidative stress, enhance neurotransmitter release, and cause apoptosis in some cells but necrosis in others.
A first-and-foremost plinth supporting the β Hypothesis is the fact that mere mutations in BAPP can cause AD. No other evidence is as persuasive or direct; BAPP is a direct player in AD. Hence, it is just a matter of figuring out how this molecule plays its role.

Third-party perspective: Whether or not each "story" of β neurotoxicity is valid or not, the practice of evaluating each one critically is essential. There is such a fog of seemingly positive results that one may be led to think that they all are true, which is almost certainly not the case. After all is said and done, the β peptide could be practically inert.

ii. The studies that have revealed neurotoxicity of β have used concentrations of the peptide that are much higher than are probably found in vivo.

"Pro β" response: As stated in the review article, the focal concentration of β (in a plaque) is probably much greater than that of CSF of AD patients, and is more likely to contai polymerized β.

Third-party perspective: Such differences between preparations of β exist that they shouldn't be cited in the same breath.

iii. If the β must be polymerized into fibrils (out of solution), it contradicts studies that suggest that specific receptor(s) are being stimulated by β.

"Pro β" response: Both could be true: certain types of toxicity could be stimulated by β in solution interacting with specific ligands; and polymerized β could cause neurotoxicity also.

Third-party perspective: This debate is the product of a difficult peptide preparation. It is hoped that this problem will resolve itself. Otherwise, it will never be clear what, in β preparations, is apparently causing toxicity.

iv. In vivo, β does not appear neurotoxic (transgenic mice, dogs, β injections).

"Pro β" response: In vivo, β transgenic mice do indeed demonstrate neuritic-like plaques, albeit without a PHF component ("neuritic" may be said to refer to dystrophic neurites, which are indeed surrounding some plaques in β transgenic mice). Moreover, in a paper not cited in the review, a transgenic β mouse was shown to develop widespread apoptotic cell death (La Ferla et al, Nature Genetics 9[1] 1995:21-30. Abstract.). Rhesus monkeys, which develop amyloid plaques, undergo mild loss of cognition in old age. And isn't it true, "you can't teach an old dog new tricks"?

Third-party perspective: A difficulty with demonstrating toxicity in vivo is that the relevance to AD is hard to assess. Even if you had a model with plaques and tangles, could you say that you had a true model of AD? After all, some think the processes are independent of each other. Until the true "key" is found, one can only try to discover that key, or put bandaids onto epiphenomena.

2. The importance of β(1-42) in the AD research world may be overblown.

i. Good circumstantial evidence exists that β(1-42) is important in AD plaques; however, the "smoking gun" of toxicity remains elusive.

"Pro β" response: β(1-42) is enriched in neuritic plaques, appears to seed further amyloid deposition, and seems to be toxic in vitro and in vivo. As yet, this still appears the closest thing to a "smoking gun".

Third-party perspective: It's very difficult to find a smoking gun, without finding an antidote that cures AD. Otherwise, one is never sure...

ii. The correlation of amyloid burden and AD dementia has been consistently shown to be poor.

"Pro β" response: Some recent studies underscore the obvious (albeit tautological): you don't have Alzheimer's without amyloid plaques. Moreover, the relation between amyloid burden and dementia is fairly good in some areas of brain. Finally, there may be some turnover of plaques (more so than tangles), which would render it impossible to gauge plaque burden to antemortem dementia.

Third-party perspective: The correlation of amyloid burden with antemortem dementia is the type of finding that depends critically upon neuroanatomy. Certain areas, as demonstrated by many people, develop plaques faster than others.

iii. Tangles and plaques can exist independently of each other.

"Pro β" response: The evidence of tangles occurring without plaques (as publicized by the Braaks [ref. 51 in the review article]), was argued against by Dr. Selkoe in an Alzheimer Research Forum discussion last year. He made the following three points (which I here paraphrase, with apologies to Dr. Selkoe):

a: Tangles occur in lots of neurological disorders. Perhaps the plaque-free brains with tangles would never develop AD.

b: Perhaps there was some amyloid in the Braak brains in areas they didn't stain.

c: Perhaps there were small β deposits not detectable by microscopy that were present in the Braak brains.

Third-party perspective: Apparently, low levels of tangles can occur without any plaque burden with aging. As amyloid burden increases, tangle formation accelerates. This is not such a bash on the β Hypothesis people. Neurons are vulnerable to tangle formation, which kills cells. Plaques cause more tangles to form, leading to dementia.

iv. Evidence that presenilin (PS) mutations increase the ratio of β(1-42):β(1-40) in cells is rendered less impressive by the data showing that simply increasing the amount of wild-type PS in cells and animals leads to increased ratios of β(1-42):β(1-40).

"Pro β" response: PS mutant transgenic mice develop amyloid plaque-like structures, whereas wt PS transgenic mice do not appear to do so.

Third-party perspective: PS seems to affect APP processing. This may or may not directly increase β(1-42), but the point is valid that PS studies more support than detract from the β Hypothesis.

v. The data that show AD patients have increased β in plasma and CSF (in comparison to controls) can be explained by other grounds than a causal role of β in AD.

"Pro β" response: The increased β in AD patients' plasma and CSF are not data integral to the Amyloid Cascade Hypothesis. However, it is intriguing that FAD patients have discernible rises in β in their plasma prior to appearance of AD symptoms.

Third-party perspective: The presence, or lack, of β in the plasma or CSF of AD patients is so fraught with variations, and possibilities for errant analysis, that it those data are hard to interpret.

3. Animal models don't support the β hypothesis.

i. Transgenic animals with upregulated β don't exhibit neuronal loss.

"Pro β" response: Transgenic animals with upregulated β do indeed have neuritic plaque-like structures and inflammation. Moreover, as stated above, transgenic mice with β do indeed exhibit neuronal loss, apoptosis, plaque-like structures, and gliosis (La Ferla, ibid.)

Third-party perspective: Transgenic animals with upregulated β have plaques that have dystrophic neurites. Now, this begs two questions: first, is it intracellular or extracellular β that is the culprit in AD? This is, perhaps, the understated main point that the present review is hammering home. An increasing stream of data supports the notion that INTRAcellular β (or some other BAPP product) could be the culprit in AD. Even if this were true, I don't think that β Hypothesis people such as Dr. Selkoe would be totally perplexed; he and others have been working on intracellular APP trafficking for years.
It is hard for anyone who has seen neuritic plaques to disbelieve that it is an important nidus of Alzheimer pathology. Not only are they an ugly bruise in the neuropil, but they are intimately associated with PHF-containing dystrophic neurites, and tend to connect anatomically with areas where tangles form. It is difficult to wave away the importance of animal models with β-containing neuritic plaque-like structures; and it is hard to accept an animal model that lacks these pathological hallmarks.

ii. The behavioral deficits seen in transgenic animals with upregulated β may not be specific, nor related exclusively to β production.

"Pro β" response: In the case of β transgenic mice with behavioral deficits, it is intriguing that without any discernible neuropathology (in contrast to animals with, say, massively upregulated neurofilament protein), β upregulation can induce behavioral deficits. Again, this is not a datum on which the β Hypothesis hangs its hat.

Third-party perspective: Evaluating behavioral deficits in mice is a nightmare. Until a pathological explanation for behavioral changes can be found, I think they are basically not very interpretable.

iii. Transgenic APP C100 mice appear to be a more faithful model of AD than transgenic mice with just β.

"Pro β" response: Transgenic APP C100 mice, despite their attractive pathological features, lack neuritic-like plaques, which are considered a fundamental neuropathological feature of AD. This is admittedly a circular argument; however, if it is hypothesized that neuritic plaques are NOT fundamental to AD neuropathology, then the burden of proof must be assumed by those who go against data-supported dogma.

Third-party perspective: See comment under 3.i above.

4. Data supports mechanisms other than those involving β (1-42) in AD neuropathology.

i. Errant trafficking of secretory vesicles through Golgi, endoplasmic reticulum could be responsible for AD pathobiology, as "all known FAD mutations occur in transmembranes that are also found in secretory vesicles".

"Pro β" response: Many proteins go through the secretory system in neurons, but ApoE does not appear to be one of them. Genetics is certainly the area which most supports the β hypothesis. Not only do APP mutations cause AD (this point is so pivotal to the β Hypothesis that it is a pity it was not addressed in the present review), but the other FAD mutations, and also Down syndrome patients, tend to further bolster the link between β production and Alzheimer's disease.

Third-party perspective: It is almost certain that intracellular trafficking plays a role in AD, either within or without the β Hypothesis. Proponents of that hypothesis are not invested in that being not the case.

ii. The normal function of PS and/or APP proteins may be disrupted, causing the pathology of AD.

"Pro β" response: If AD were a "loss of function" disease, the production of β could still be fundamental in proteins (including APP and PS) losing their functions.

Third-party perspective: Although β could be a factor in causing "loss of function" changes in AD, the elucidation of those changes could be the necessary key in finding a cure for the disease. Even if such a change were "downstream" of β formation, there could be a spiraling-downward loop which could be altered.

iii. Apoptotic mechanisms may be responsible that are independent of the β per se (involving either APP-->Go--> apoptosis, PS-->apoptosis, a/o other mechanisms).

"Pro β" response: Most currently-proposed mechanisms of apoptotic cell death currently include a place for β. And again, if APP or PS cause apoptosis in AD brain, surely the disruptive influence of β plaques helps lead to that end.

Third-party perspective: The knowledge about apoptosis in the aged brain is more sketchy than most people seem to admit. "Classical apoptosis" could quite simply not occur there. However, in the context of the current debate, were apoptosis to be relevant to AD, β could play a role at many levels.

iv. A myriad of non-β(1-42) mechanisms have recently been put forward for the majority of AD victims that suffer from late-onset disease; these include "inflammatory processes, oxidative damage, and mitochondrial mutations", in addition to Apo E-related mechanisms and others.

"Pro β" response: It is clear that only a minority of FAD cases are caused by BAPP mutations; hence, the β production will be "downstream" of some changes (e.g. mitochondria mutations, Apo E mechanisms) and "upstream" of others (e.g. oxidative stress, inflammatory processes). The fact that in the chaos of the AD brain many changes are noted does not subtract from there being a fundamental role for β in causing that chaos.

Third-party perspective: AD is obviously a heterogeneous disease, as noted by the review authors. Much remains to be learned. It is notable that the current discussants, Drs. Neve, Robakis, and Selkoe, are among the most preeminent and capable of the scientists searching for new knowledge in the field.

	Comments on Live Discussion
	Comment by:  Andre Delacourte
	Submitted 30 July 2004  |  Permalink	Posted 30 July 2004
	The amyloid cascade hypothesis (ACH) does not fit with the natural and molecular history of Alzheimer's disease. Major points: The first argument against the ACH is that tau and APP pathologies always grow in parallel in the human brain (Delacourte A, et al, Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer's disease.Neurology. 2002 Aug 13;59(3):398-407). However, in sporadic AD, you can find tau pathology (in the entorhinal and hippocampal regions) without any trace of amyloid deposits, while the opposite is not true. Furthermore, the evolution of the clinical impairments is fully explained with the progression of tau pathology in specific brain areas (Braak stages I to VI; Delacourte stages 1 to 10). Indeed, ACH derives from and is adapted to familial AD and the mutations on APP and PS1. However, even for these genetic cases, the clinical expression appears (generally around the age of 45 years) with the sudden development of tau pathology in neocortical areas. Of course, APP dysfunction is instrumental in the etiology...  Read more The amyloid cascade hypothesis (ACH) does not fit with the natural and molecular history of Alzheimer's disease. Major points: The first argument against the ACH is that tau and APP pathologies always grow in parallel in the human brain (Delacourte A, et al, Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer's disease.Neurology. 2002 Aug 13;59(3):398-407). However, in sporadic AD, you can find tau pathology (in the entorhinal and hippocampal regions) without any trace of amyloid deposits, while the opposite is not true. Furthermore, the evolution of the clinical impairments is fully explained with the progression of tau pathology in specific brain areas (Braak stages I to VI; Delacourte stages 1 to 10). Indeed, ACH derives from and is adapted to familial AD and the mutations on APP and PS1. However, even for these genetic cases, the clinical expression appears (generally around the age of 45 years) with the sudden development of tau pathology in neocortical areas. Of course, APP dysfunction is instrumental in the etiology of AD. But our hypothesis is that the defect is related to a loss of function of APP, via its carboxy-terminal fragments (APP-CTFs) that disappear in quality and quantitiy in FAD and sporadic AD (Sergeant N et al. Progressive decrease of amyloid precursor protein carboxy terminal fragments (APP-CTFs), associated with tau pathology stages, in Alzheimer's disease. J Neurochem. 2002 May;81(4):663-72). A participation of amyloid deposits is not excluded, but more likely at the last stages. In short, AD is a true tauopathy fueled by APP dysfunction (Delacourte & Sergeant, Brain Aging, 2004, vol 4, N°1, 15-21). References: Sergeant N, David JP, Champain D, Ghestem A, Wattez A, Delacourte A. Progressive decrease of amyloid precursor protein carboxy terminal fragments (APP-CTFs), associated with tau pathology stages, in Alzheimer's disease. J Neurochem. 2002 May;81(4):663-72. Abstract View all comments by Andre Delacourte

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