4 ms·

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-

by pcrh 4mo ago

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/ https://pubmed.ncbi.nlm.nih.gov/25743013/

DavidSJ 4mo ago
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.
- dekhn 4mo ago
  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.
- pcrh 4mo ago
  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 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/ 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/ https://pmc.ncbi.nlm.nih.gov/articles/PMC12017768/
- pcrh 4mo ago
  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-fragments-stifle-calcium-flow-er-lysosomes https://www.alzforum.org/news/research-news/app-c-terminal-f...

by pcrh 4mo ago

DavidSJ 4mo ago

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.

dekhn 4mo ago
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.
pcrh 4mo ago
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 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/ 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/ https://pmc.ncbi.nlm.nih.gov/articles/PMC12017768/
pcrh 4mo ago
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-fragments-stifle-calcium-flow-er-lysosomes https://www.alzforum.org/news/research-news/app-c-terminal-f...