Hacker News Board Hacker News, browsed like a classic message board
Live data from Hacker News

Copper transport drug restores memory and clears toxic Alzheimer's proteins

monash.edu

Post reply on HN
Print view View original

141–150 of 150 posts

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#141

Post by pcrh »

DavidSJ wrote: post #140
pcrh wrote: post #139

Earlier quoted context omitted.

Yes, there is a clear sequence of how AD pathology develops, starting with amyloidopathy and progressing to tauopathy, but 1) there is as yet no established molecular connection between the two, and 2) one should not conflate pathology with disease mechanisms. So, taking the amyloid hypothesis itself (putting presenilin aside for the time being). We know that mutations in APP do cause AD. How? And if amyloid is not t…

Yes, there is a clear sequence of how AD pathology develops, starting with amyloidopathy and progressing to tauopathy, but 1) there is as yet no established molecular connection between the two, and 2) one should not conflate pathology with disease mechanisms. I agree that the specific molecular mechanism(s) is/are currently unknown. I've seen a number of proposals, but to my knowledge there isn't smoking-gun evidenc…

These points still don't explain how mutations in APP cause AD.

Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. (One can ignore claims that this mutation increases Abeta oligomers, since the evidence is that Abeta oligomers are found at far too low concentrations in the human brain. They would have to be more toxic than ricin if they were etiological for AD). The oligomers seen on gels are an artefact, see the controversy surrounding Tessier-Lavigne).

As you state, and I agree, APP is upstream of tau in natural AD pathogenesis, but does not cause neurodegeneration in mice. So we still don't know from direct experimentation how APP leads to tauopathy and neuodegeneration. The evidence that this is through Abeta per se is tentative at best.

[0] A Second Pedigree with Amyloid-less Familial Alzheimer’s Disease Harboring an Identical Mutation in the Amyloid Precursor Protein Gene (E693delta) https://pubmed.ncbi.nlm.nih.gov/25743013/

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#142

Post by DavidSJ »

pcrh wrote: post #141
DavidSJ wrote: post #140

Earlier quoted context omitted.

Yes, there is a clear sequence of how AD pathology develops, starting with amyloidopathy and progressing to tauopathy, but 1) there is as yet no established molecular connection between the two, and 2) one should not conflate pathology with disease mechanisms. I agree that the specific molecular mechanism(s) is/are currently unknown. I've seen a number of proposals, but to my knowledge there isn't smoking-gun evidenc…

These points still don't explain how mutations in APP cause AD. Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. (One can ignore claims that this mutation increases Abeta oligomers, since the evidence is that Abeta oligomers are found at far too low concentrations in the human…

Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0].

This is interestingly similar to the Arctic Mutation, and in the same codon no less: no plaque, but still autosomal-dominant AD due to an APP mutation. I had previously taken the Arctic Mutation to be evidence that it's not plaque per se, put more likely protofibrils (which are components of plaques in normal AD, and still present under the Arctic Mutation) or precursor aggregates which are pathogenic. The fact that the Osaka Mutation blocks protofibril formation underlines the uncertainty, that you and I agree exists, on the detailed molecular mechanisms. I would be inclined to point then to oligomers, but you say the oligomers are found at far too low concentrations to be relevant — what's your source for this?

As you state, and I agree, APP is upstream of tau in natural AD pathogenesis, but does not cause neurodegeneration in mice. So we still don't know from direct experimentation how APP leads to tauopathy and neuodegeneration. The evidence that this is through Abeta per se is tentative at best.

Not only APP, but also PS1+PS2 mutations of course, can cause ADAD, and the relevant mutations all seem to cause more Abeta42 production. In the sporadic case, production usually seems unchanged, but clearance is usually impaired (especially with ApoE4). What they all seem to have in common is amyloid production or clearance. I'm curious if you know of another pathway they have in common besides this. Otherwise it's hard to see what the alternative hypothesis is, which could explain the etiology of seemingly highly-similar disease trajectories (ADAD + sporadic AD).

I’ll add as an addendum: APP mutations do cause neurodegeneration in mice, if those mice are combined amyloid+tau models. This seems most faithful to the human disease.

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#143

Post by dekhn »

DavidSJ wrote: post #142
pcrh wrote: post #141

Earlier quoted context omitted.

These points still don't explain how mutations in APP cause AD. Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. (One can ignore claims that this mutation increases Abeta oligomers, since the evidence is that Abeta oligomers are found at far too low concentrations in the human…

Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. This is interestingly similar to the Arctic Mutation, and in the same codon no less: no plaque, but still autosomal-dominant AD due to an APP mutation. I had previously taken the Arctic Mutation to be evidence that it's not plaq…

At this point you should just go to grad school in a molecular neurology program. You clearly have the passion for this sort of research, and it would probably be useful to immerse yourself in the process to get more experience and judgement. Grad programs in bio usually have journal clubs; bring one of your papers, and see what people think of it.

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#144

Post by DavidSJ »

xenadu02 wrote: post #138
DavidSJ wrote: post #79

Earlier quoted context omitted.

Now if we consider amyloid beta therapies: we have treatments that target amyloid beta with varying degrees of success but at least some show definite reductions in amyloid beta plaques. To the best of my knowledge that has not shown to improve outcomes in Alzheimer's patients to any meaningful degree. This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed…

> This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed in the article. Perhaps I am just not well-informed but 30% slowdown in progression translates to sufferers have some mild improvement in cognitive tests and live a few months longer. Maybe it is simply too early to tell but I would naively expect something much more significant. Perhaps this is the…

Perhaps I am just not well-informed but 30% slowdown in progression translates to sufferers have some mild improvement in cognitive tests and live a few months longer.

A few years longer. It's obviously frustratingly far from where we'd like to be. It was only a direct response to the claim that Alzheimer treatment isn't even in the "sometimes progress is slow" category, but rather in the "no meaningful benefit at all" category.

I'm not saying amyloid beta research should be terminated. Merely that everyone in the field should be willing to entertain other ideas.

We agree that people should be willing to entertain other ideas! I don't think anyone is saying otherwise.

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#145

Post by armadsen »

avgDev wrote: post #127
armadsen wrote: post #92

Earlier quoted context omitted.

My wife’s family has PSEN1-mutation EAD (my wife didn’t inherit it). In that particular case it does seem that the mutated genes relate directly to Amyloid production and clearing, and there are ongoing clinical trials for the use of the new monoclonal antibody drugs in treating it. Two of my family members are in a trial for Remternetug, specifically. There is hope that in that specific case where 1. Amyloid buildup…

Are you family members experiencing any symptoms of the disease? I guess if my mother has the gene I will test for PSEN1 at some point, but I am worried about the side effects of the meds. Hope things go well for your family.

My father in law passed away from it about a year and a half ago at age 64. Two of his kids have tested positive for the mutation. They don’t have symptoms yet (they’re in their 20s and 30s).

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#146

Post by pcrh »

DavidSJ wrote: post #142
pcrh wrote: post #141

Earlier quoted context omitted.

These points still don't explain how mutations in APP cause AD. Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. (One can ignore claims that this mutation increases Abeta oligomers, since the evidence is that Abeta oligomers are found at far too low concentrations in the human…

Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. This is interestingly similar to the Arctic Mutation, and in the same codon no less: no plaque, but still autosomal-dominant AD due to an APP mutation. I had previously taken the Arctic Mutation to be evidence that it's not plaq…

No APP-alone mouse gets neurodegeneration resembling that seen in the human AD brain, i.e. with so-called "neuritic" plaques, tauopathy, spongiopathy and widespread neuronal death.

This is why researchers now most often use the 5XFAD mouse, which has APP with three mutations, and presenilin with two mutations (hence 5 FAD mutations) [0]. Note however that mutated presenilin alone is enough to cause neurodegeneration in mice, such mice however do not accumulate amyloid, which is why mutated APP in added to make the pathology more "realistic".

As to Aβ42, there are mutations in APP which cause familial AD, but produce exclusively Aβ40, e.g. APP A673V [1]. Note also that most studies report alterations in the ratio of Aβ42 to Aβ40, precisely because effects on the levels of Aβ production are inconsistent across APP mutations.

Nevertheless..... and despite my obvious skepticism towards the amyloid toxicity hypothesis, the mutations in APP that cause AD all cluster in or near the region of the protein that is Aβ. There must be a reason for that. It is also in contrast to presenilin, where the mutations are distributed throughout the molecule, indication a loss of presenilin function causes AD.

One alternate explanation to Aβ or oligomer toxicity is proposed toxicity of the immediate precursor to Aβ, i.e. the APP C-terminal fragment (CTF), see for example the recent paper below and references therein [2].

[0] https://www.alzforum.org/research-models/5xfad-b6sjl

[1] A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis https://pmc.ncbi.nlm.nih.gov/articles/PMC2728497/

[2] APP β-CTF triggers cell-autonomous synaptic toxicity independent of Aβ https://pmc.ncbi.nlm.nih.gov/articles/PMC12017768/

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#147

Post by pcrh »

DavidSJ wrote: post #142
pcrh wrote: post #141

Earlier quoted context omitted.

These points still don't explain how mutations in APP cause AD. Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. (One can ignore claims that this mutation increases Abeta oligomers, since the evidence is that Abeta oligomers are found at far too low concentrations in the human…

Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. This is interestingly similar to the Arctic Mutation, and in the same codon no less: no plaque, but still autosomal-dominant AD due to an APP mutation. I had previously taken the Arctic Mutation to be evidence that it's not plaq…

P.S.

As you have demonstrated an interest in this topic, but are not an active researcher, I suggest that you become familiar with Alzforum [www.alzforum.org]. It provides reputable summaries and comments from leading researchers on topical issues and papers in Alzheimer's and related neurodegenerative diseases.

They're still fairly technical, but not as dense as the original papers. Here is an example related to our discussion: https://www.alzforum.org/news/research-news/app-c-terminal-f...

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#148

Post by DavidSJ »

pcrh wrote: post #147
DavidSJ wrote: post #142

Earlier quoted context omitted.

Note that not all AD-causing mutations in APP also cause amyloid accumulation, for example APP-Osaka (loss of APP residue E693) results in familial AD without any accumulation of amyloid [0]. This is interestingly similar to the Arctic Mutation, and in the same codon no less: no plaque, but still autosomal-dominant AD due to an APP mutation. I had previously taken the Arctic Mutation to be evidence that it's not plaq…

P.S. As you have demonstrated an interest in this topic, but are not an active researcher, I suggest that you become familiar with Alzforum [www.alzforum.org]. It provides reputable summaries and comments from leading researchers on topical issues and papers in Alzheimer's and related neurodegenerative diseases. They're still fairly technical, but not as dense as the original papers. Here is an example related to our…

I've been a regular reader of Alzforum, and cite multiple of their articles in the blog post that was linked up above. https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#149

Post by pcrh »

DavidSJ wrote: post #148
pcrh wrote: post #147

Earlier quoted context omitted.

P.S. As you have demonstrated an interest in this topic, but are not an active researcher, I suggest that you become familiar with Alzforum [www.alzforum.org]. It provides reputable summaries and comments from leading researchers on topical issues and papers in Alzheimer's and related neurodegenerative diseases. They're still fairly technical, but not as dense as the original papers. Here is an example related to our…

I've been a regular reader of Alzforum, and cite multiple of their articles in the blog post that was linked up above. https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...

Thanks for the article.

I actually read your article some time ago, having found it via SSC. One comment I would make is that the pathology and genetics of AD implicate APP without much doubt. In the field, there isn't much argument against it, even by those who work on tau. Divergences in opinion more often focus on which is the better target for drug therapy.

For example, Derek Lowe's articles on AD do not argue against an APP-tau-neurodegeneration pathway (I am a regular reader of his blog), but argue that targeting amyloid is unlikely to work as a drug therapy. This argument is sometimes extended by Lowe and others to questioning whether Aβ per se is the agent that triggers the downstream effects of either mutating APP or otherwise disrupting its biology. It is possible that Aβ is a by-product of the "true" APP-triggered pathway, see the arguments in favor of C-terminal fragments I linked to earlier.

A fundamental problem the field faces is that it is difficult to experimentally induce actual AD in animals, and so it is difficult to scientifically test hypotheses as to what might cause it. Compare perhaps to something like diabetes. Exactly why mice do not develop realistic AD is unknown.

In addition, there have been literally hundreds of publications (minimum 300) claiming to reverse "Alzheimer's disease" in mice, and the only ones that have lead to any kind of meager success are those using the antibodies. The arguments made in the 2010 review below by Zahs and Ashe [0] remain mostly true sixteen years later.

The recent clinical trials, e.g. Lecanemab, are of interest not only because they might provide at least some benefit, but also because they might represent the first actual scientific experiments showing that removing Aβ can ameliorate the disease, even if only slightly because of the late stage at which they have so far been tested.

Currently ongoing trials using anti-Aβ antibodies and targeting earlier phases of the disease in those with inherited mutations are of keen interest. If these demonstrate clear prevention of disease progression, then the Aβ hypothesis can be considered tested and proven. If not, then the Aβ hypothesis should be abandoned. This would however still not disprove an APP-focused hypothesis.

[0] 'Too much good news' - are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer's disease? https://alzped.nia.nih.gov/sites/default/files/2022-09/zahs....

Re: Copper transport drug restores memory and clears toxic Alzheimer's proteins

#150

Post by computerdork »

dekhn wrote: post #54
DavidSJ wrote: post #44

Earlier quoted context omitted.

This frequently comes up as a critique of my article, but I don't claim to be disrupting the field as a smart outsider. Rather, I looked at the field and concluded that the experts seem to know what they're doing. Derek Lowe is very much in the minority on this matter.

No, he's not (I work in pharma at a company that does basic and applied research on Alz). It's more correct to say there are several camps, but the camp promoting amyloid plaques as the causative/driver for Alz has struggled greatly to come up with evidence supporting its position.

This is of course an older thread, but wanted to ask you, what are the major camps in Alz these days?

...and had also heard about how amyloid research had been based on bad/fraudulent research. One of the biggest scandals was by Tessier-Lavigne from Stanford, correct?

Post reply on HN