6 ms·
Molecule restores cognition, memory in Alzheimer's disease model mice
- gilleain 2y agoFrom the paper :https://pubmed.ncbi.nlm.nih.gov/39106304 https://pubmed.ncbi.nlm.nih.gov/39106304 edit: ok apologies, after several attempts http://www.chemspider.com/Chemical-Structure.24670873.html http://www.chemspider.com/Chemical-Structure.24670873.html 3-(2-Naphthylmethyl)-4-(4-piperidinyl)-1H-pyrazol-1-ol (incorrect stuff removed ...)
- A_D_E_P_T 2y agoThat's not the one. The fulltext of the paper is here: https://www.pnas.org/doi/10.1073/pnas.2400420121#supplementary-materials https://www.pnas.org/doi/10.1073/pnas.2400420121#supplementa... The structure is in the SI. You can draw it with SMILES code: On1cc(c(n1)Cc1ccc2c(c1)cccc2)C1CCNCC1 At: https://www.antvaset.com/smiles-to-structure https://www.antvaset.com/smiles-to-structure
- gilleain 2y agooops. shouldn't try 'research' on my phone. thanks. Incidentally, I'm sure it used to be possible to google search using InChI. Even using the InChI-Key now doesn't work super well it seems. I have to quote it to get this PubMed link: https://pubchem.ncbi.nlm.nih.gov/compound/46204539 https://pubchem.ncbi.nlm.nih.gov/compound/46204539 which actually gives a link to the patent : "Compositions and methods for treating neurodegenerative diseases"
- RobotToaster 2y agoWould it be naive to say it looks like quite a simple (and ergo, cheap) molecule to synthesise?
- jdoe2020 2y agoShouldn't be too bad. My gut would be toa naphthalene acetic acid ester, treat with LDA, add (4-pyridinyl)acetaldehyde to get a diketone by claisen-type condensation, then treat with hydroxylamine then reflux with hydrazine to form the pyrazole not sure how you would get the n-oxide but there is likely a selective oxidant available. The n oxide kind of scares me a bit. Seems like it could have some interactions with liver enzymes. Usually you avoid them if you can.
- cornholio 2y agoSeems different from what they claimed as DDL-920 in their patent (but I'm not a chemist): https://patents.google.com/patent/WO2022226172A1/en https://patents.google.com/patent/WO2022226172A1/en
- amluto 2y agoIt can join this one: https://pubmed.ncbi.nlm.nih.gov/26439832/ https://pubmed.ncbi.nlm.nih.gov/26439832/ The obvious major caveat is that mice are not people, and that mouse models of what someone thinks are Alzheimer’s-like diseases are not people with Alzheimer’s.
- newzisforsukas 2y agoJoin it how? They seem like very different studies and mechanisms.
- welfare 2y agoI think they meant join in the sense of yet another study performed on mice with promising results without any indication if it will work in humans. Come back after clinical trials. Breakthroughs in Alzheimer's seems like the medical equivalent of breakthroughs in battery tech.
- newzisforsukas 2y ago... no one is calling this a breakthrough though? The paper itself and the article on it both state it is in mouse models of disease within their titles. Seems like many here bring up this point for no reason other than to repeat it over and over as a low-effort dismissal. It is exhausting to read these threads. At the moment I am writing this, there is only a single comment about the actual article.
- gdudeman 2y agoI wish breakthroughs in Alzheimer's were like breakthroughs in battery tech. Batteries are getting dramatically cheaper and denser every year with a clear path for 10+ years of improvements. Alzheimer's treatments today maybe slow cognitive decline by 3 months and cost a fortune.
- amluto 2y agoJoin as a promising small molecule that seems to treat a disease in mice that may be related to Alzheimer’s.
- engine_y 2y agoThanks for having 'in model mice' in the header. Unfortunately mice disease models have not been showing efficacy in humans.
- bawolff 2y agoI don't think that is true in general, it more depends on the disease in question.
- mbStavola 2y agoGetting ahead of the "in mice" meme replies, it is nice to see further developments in the search for a cure.
- ben_w 2y agoAye. Lost my mum to that in the middle of the pandemic. Long mental decline including hemispatial neglect*, but physically (mostly) fine right up until the last few days in the care home, when she forgot about drinking — though we had to work that out much later and from the autopsy as nobody around her could reasonably have watched her 24/7 to count glasses of water not consumed. * such a bizarre thing to witness: her sitting at the dinner table, the food eaten on only one side of her plate while the other side was full, and her insisting the plate was empty until one of us rotated it 180°.
- Bluestein 2y agoSo sorry about your loss.-
- Kuinox 2y agoI do comment "in mice" when the title doesn't contain "in mice" when it should. I see it as misleading if it doesn't contain it.
- Bluestein 2y agoWe've downgraded even, from "in mice" to "in mice models" ... ... don't even test on real mice anymore.-
- londons_explore 2y agoI do wonder if medicine would do better if we simply skipped the efficacy tests in animals (due to the very low accuracy of animal models of diseases not well understood) and simply did animal safety tests, then moved straight onto human trials. Obviously the vast majority of treatments would be ineffective - and this in turn should let you design multi-treatment trials, where say a trial of 100 patients are used to test 50 substances, with each person receiving simultaneously tiny doses of ~25 candidate treatments. Then the patient outcomes are used to identify which of the 50 likely have some effect, and a trial is done of just that substance.
- nonrandomstring 2y agoIt does some anomalous that some states are moving toward assisted dying which (I don't personally agree with for complex reasons), which is essentially a very humane stance, and yet elderly people or those who are terminally ill cannot, it seems, waive their "safety right" under law and consent to be trial subjects for experimental drugs with high risks.
- unsupp0rted 2y agoIn Canada there's assisted dying for people with mental illness: perfectly physically healthy people, who might even decide to live a fair bit longer if they felt they were contributing to saving lives by allowing testing.
- mtlmtlmtlmtl 2y agoI'm not sure what you're even suggesting here. First of all, according to the canadian government[1], euthanasia is not currently permitted in cases only involving mental illness. It's been delayed twice already, currently until 2027, and may be delayed further or scrapped entirely in the future for all we know. Second, what would they be testing? Drugs for their condition? That wouldn't apply to the type of situation necessary for euthanasia under Canadian law[2]: >To be considered as having a grievous and irremediable medical condition, you must meet all of the following criteria. You must: 1. have a serious illness, disease or disability 2. be in an advanced state of decline that cannot be reversed 3. experience unbearable physical or mental suffering from your illness, disease, disability or state of decline that cannot be relieved under conditions that you consider acceptable If there was an experimental treatment that might actually help them, these criteria would not apply. If you're suggesting safety testing of drugs for other illnesses, that's extremely unethical and I seriously doubt the medical community would be willing to do it, even with consent. And I seriously doubt a number of people large enough to give meaningful results would consent in the first place. It's also of dubious usefulness because any treatment intended for disease X might have its safety profile and risk/benefit analysis altered by the presence or non-presence of X. 1: https://www.canada.ca/en/health-canada/services/health-services-benefits/medical-assistance-dying/legislation-canada.html https://www.canada.ca/en/health-canada/services/health-servi... 2: https://www.canada.ca/en/health-canada/services/health-services-benefits/medical-assistance-dying.html#a2 https://www.canada.ca/en/health-canada/services/health-servi...
- Beijinger 2y ago"Wei et al., have studied the subunit composition of γ-aminobutyric acid type A receptors responsible for the tonic inhibition of parvalbumin positive interneurons and identified a small molecule (DDL-920) as a potent, efficacious, and selective negative allosteric modulator of these receptors." A SMALL molecule? And not formula? Odd.
- dillydogg 2y agoI the term small molecule has a specific meaning in biopharma and the biochemical formula is almost certainly not going to reveal much information. Might as well just use the convention of the compound ID. Related, in the supplemental data the compound's reference is Ref XX. Must have slipped by the reviewers.
- robwwilliams 2y agoThat error is on the PNAS editorial team - not on the reviewers.
- aftbit 2y agoI'm not entirely sure I understand your comment, but "small molecule" is a drug discovery term of art, and includes things with relatively high molecular weights and complex formulae. Anything sub-1000 daltons is generally considered a "small molecule". https://en.wikipedia.org/wiki/Small_molecule https://en.wikipedia.org/wiki/Small_molecule
- Beijinger 2y agoWith a PhD in Chemistry, I understand what a "small molecule" is. But by looking at the link for a few seconds, I found no further information about the compound. I am not a big fan of "secret sauce". Maybe I missed it in the paper.
- jdoe2020 2y agoYeah I was looking for that but didn't find it in the paper, someone else here linked to pubchem in this thread. It's 3-(4-pyridinyl)-2-(napthylmethyl)-pyrazole N-oxide or something like that. My IUPAC is a bit rusty
- harles 2y agoI love that “in mice” is in the title (both on HN and in the original article). It seems like a promising result and I really appreciate them not over hyping it.
- RivieraKid 2y agoAlzheon's ALZ-801 pill should be approved within a year and should be basically an Alzheimer cure for 15% (current phase 3 trial) and later 2 thirds of people. I've recently learned about this and was surprised it's somewhat under the radar. Am I missing something?
- robwwilliams 2y agoThe fundamental problem of the great majority of so-called “in mice” studies is their use of exactly 1 (one) fully inbred type of mouse — C57BL/6J. Would you trust N=1 clinical trials? In this particular PNAS study you have to be hard-core reader and rummage around in the Methods section to uncover this awkward detail: “Mouse strains used were C57BL/6J (Black 6, Jackson Laboratory; JAX stock #000664), JAX stock #003725 (Gabrd−/− mice on a C57BL/6J background…” No wonder translation fails so often. It is not the mice, it is scientists cutting corners! Some of us working with mice use many different genotypes of mice to ensure somewhat more robust results that have a better chance to generalize across mouse genomes and perhaps even human populations. This is not new news. Here is a classic on this topic in Alzheimer’s research published in Neuron in 2019: https://pubmed.ncbi.nlm.nih.gov/30595332/ https://pubmed.ncbi.nlm.nih.gov/30595332/ One more point: There is a great deal of variation in expression of key genes/proteins mentions in this recent PNAS study, in particular parvalbumin and the GABA receptors. For example parvalbumin protein levels in the hippocampus of different strains of mice at different ages vary over a 20-fold range. Here are the hard data from GeneNetwork.org; https://genenetwork.org/show_trait?trait_id=61839_VFHILDKDKSGFIEEDELGSILK_5&dataset=JAX-BXD-Hip-Pro-log2-0723 https://genenetwork.org/show_trait?trait_id=61839_VFHILDKDKS... And GABA receptors also have high levels of variation in hippocampus and other brain regions. Here is a good paper that compares mouse and human GABA receptor variation. https://pubmed.ncbi.nlm.nih.gov/22506031/ https://pubmed.ncbi.nlm.nih.gov/22506031/
- BenFranklin100 2y agoThis is comment is needlessly inflammatory and is not informative of how biomedical research is conducted. First, it’s important to point out to the lay reader that the reason researchers frequently use mice strains in the first place is not “to cut corners”; it as an attempt to manage the incredible variability inherent in biology, especially when one moves to complex systems like living mammals. If the mice in a study have the same genetic background, then it far more likely the effect under study can be observed, and not otherwise buried in the noise as it would if wild mouse strains were used. Using a common mouse strains helps compare studies across different areas of research too. It’s the same reason why so much research is done using HeLa cells. Your post gives the lay reader the impression the researchers were being irresponsible; rather than just using a common strain to demonstrates their point. Second, you apparently weren't being too much of a "hard core' reader (or least explainer to the lay reader) because if you had you would highlight this bit in the Methods section that list the multiple mouse models used: 1. C57BL/6J 2. Gabrd-/- mice on a C57BL/6J background 3 Pvalb-IRES-Cre mice 4. B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J 5. ApoE4-TR:5xFAD mice These are not stock C57/Bl6 mice and do carry specific mutations. Finally, as the second half of your post acknowledges and the paper demonstrates, different strains are being used in AD research. There are entire centers dedicated to developing specific mouse strains, many with humanized genes, to attempt to capture specific mutations known to be present in humans, some on C57 background, but many others that are not. Jackson labs has developed several as has several other prominent groups in the field [1]. [1] https://www.jax.org/news-and-insights/2024/july/researchers-are-closing-in-on-a-mouse-model-for-alzheimers-research https://www.jax.org/news-and-insights/2024/july/researchers-...; https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.056498 https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz... Lastly, I have no idea if this paper is any good.
- trhway 2y ago>Auditory, visual or transcranial magnetic stimulation at a frequency of 40 Hz – similar to the frequency of a cat’s purr – worked to dissolve plaques in the brain but again did not show notable cognitive enhancements, Mody said. my fascination with cats just got even bigger :) One can wonder whether having a cat would prevent/slow the plagues accumulation to start with.
- compressedgas 2y agoNot unless your cat purrs magnetic fields in the Tesla range.
- trhway 2y agoyou somehow missed auditory and visual. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9759142/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9759142/ "Gamma oscillations and application of 40‐Hz audiovisual stimulation to improve brain function" "Currently, 40‐Hz audiovisual stimulation was demonstrated to affect synaptic plasticity and modify the connection status of related brain networks in animal experiments and clinical trials."
- compressedgas 2y ago> Auditory, visual or transcranial magnetic stimulation at a frequency of 40 Hz I read that as: transcranial magnetic stimulation of auditory or visual at a frequency of 40 Hz I would not have misread: Stimulation auditory, visual or transcranial magnetic at a frequency of 40 Hz this would break up the noun phrase which was the cause: transcranial magnetic stimulation
- xpl 2y agoHow did they induce Alzheimer's in a mouse to begin with? I thought we still do not understand the causes, so how could they possibly do that?