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Posted On: 03/06/2024 10:16:40 PM
Post# of 148878
Re: mightycydy #141538
mighty,
This is what Dr J said Ed: Alzheimer’s and LL. I also think I think you have the right paper from 6/22. Both are mice related. The paper reports an intensely prosecuted mice study regarding CCR5/CCL5 presence and exclusion, and the memory results in test subject, mice.
Here’s Dr J from yesterday.
“And given the world's highest safety profile of Leronlimab to date, together with data from a recent preclinical study suggesting that blocking CCR5 in mice can rescue memory deficits, I believe a pilot study in Alzheimer's Disease is now justified.”
Investors Hangout: https://investorshangout.com/post/view?id=667...z8Tkf8UHFp
Here is a link to the paper you shared in case others want to read.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197199/
Ohm20 came with this paper from 11/21. Not the same, but also tested with Maravoric. Mainly going down the tech Tau/Amyloid path. I’ll share a few Maravoric citations from both later.
https://molecularneurodegeneration.biomedcent...21-00500-0
Here’s a couple of key passages from your 6/22 paper. They did a fairly exhaustive study. If they noticed a result in young mice, they tested it in old mice. If they noticed in CCR5 neg mice, they tested it in CCR5 knockout mice (Maravoric) Etc. Quite impressive results.
“Here, we report that a delayed (12-24h) increase in the expression of the C-C chemokine receptor type 5 (CCR5), an immune receptor well known as a co-receptor for HIV infection6,7, following the formation of a contextual memory, determines the duration of the temporal window for associating or linking that memory with subsequent memories.”
“CCR5 has been extensively studied in the context of inflammatory responses and HIV infection6,7. However, comparatively little is known about its role in learning and memory. Both CCR5 and its ligand CCL5 are highly enriched in the CA1 region of the hippocampus14–16, and CCR5 is a negative regulator of CREB activation and neuronal excitability15,17. Here, we demonstrate that a gradual increase in the expression of CCL5/CCR5 following memory formation closes the temporal window for memory linking, thus segregating memories that are temporally distinct.”
“To determine whether CCR5 modulates the temporal window for contextual memory linking1, we first exposed the mice to one context (context A) and either 5h, 1, 2 or 7 days later we exposed the mice to a second context (context
(Fig. 2a). Two days later, the mice were given an immediate shock in context B, and then contextual memory linking was tested 2d later in context A.”
“During the contextual memory linking test, only the control group, but not the Opto-CCR5 group, showed evidence of memory linking (i.e., higher freezing in context A, that the mice experienced 5h before context B, compared to a novel context; Fig. 2e), confirming that increasing neuronal CCR5 activity specifically after exposure to context A is sufficient to impair contextual memory linking without impairing memory for context B.”
“Thus, two very different manipulations that decreased the levels of CCR5 (shRNA-mediated knockdown and a knockout) extended the temporal window for memory linking. Similar to Ccr5−/− mice, Ccl5 knockout (Ccl5−/−) mice also showed an extended linking window (Extended Data Fig. 6g), indicating that CCL5 is critical for CCR5 regulation of memory linking…Altogether, our results show that increasing or inhibiting CCR5 signaling impaired or extended (respectively) the temporal window for contextual memory linking, demonstrating a key role for CCR5 in setting the duration for the memory linking window.”
“This result supports the hypothesis that CCR5 activation excludes neurons from memory ensembles.”
“Altogether, the results presented suggest that the increase in CCR5 expression and signaling after learning prevents subsequent memories from being allocated to the neuronal ensemble encoding the initial memory, thus reducing the overlap between the two memory ensembles, and consequently attenuating memory linking.”
“CCR5 and CCL5 expression in peripheral immune cells increases with age31,32. Similar increases in aging neurons could contribute to age-related decreases in contextual memory linking1. To test this hypothesis, we measured hippocampal Ccr5 and Ccl5 expression in 16~18-month-old mice (middle-aged), an age in which mice still show intact contextual conditioning, but deficits in contextual memory linking”
“To test the effect of pharmacologically blocking CCR5 activity on contextual memory linking in middle-aged mice, maraviroc (an FDA approved CCR5 antagonist used for HIV treatment; Extended Data Fig. 4d–f)33 was infused to dCA1 of these mice 1h before they were exposed to context B in a contextual memory linking experiment with a 5h interval. Unlike control mice, maraviroc-treated mice showed memory linking (Fig. 4h). Thus, blocking CCR5 with maraviroc ameliorates the memory linking deficits in middle-aged mice. Altogether these results support a role for CCR5 expression in closing the temporal window for memory linking as well as in age-related deficits in memory linking.”
“In summary, the findings reported here show that a delayed (12-24h) increase in CCL5/CCR5 signaling in dCA1 neurons of a given memory ensemble closes the temporal window for memory linking. CCR5 activation decreases neuronal excitability, thus negatively regulating memory allocation. This change in memory allocation decreases the overlap between memory ensembles, and therefore impairs the ability of one memory to trigger the recall of the other, thus closing the temporal window for memory linking (Extended Data Fig. 10). Remarkably, our findings also show that an age-related increase in CCL5/CCR5 expression leads to impairments in memory linking in middle-aged mice that could be reversed with an FDA approved drug that inhibits this receptor, a result with significant clinical implications. All together the findings reported here provide the first insights into the molecular and cellular mechanisms that close the temporal window for memory linking, thus segregating the memories for events that are temporally distinct.”
Conclusion is just what Dr J said about resources.
“The challenge of course is that CytoDyn is just emerging from a two year clinical hold and doesn't have the resources to do everything we'd like. We're also keenly aware the need to stay focused and not try to do too much all at once.
But I believe we have this going forward, “Anything Maravoric can do, we can do better!” Like 100.83% better!
Running out of time for Ohms paper, but here’s a Maravoric citation from it.
“Abstract
Background
Neurocognitive impairment is present in 50% of HIV-infected individuals and is often associated with Alzheimer’s Disease (AD)-like brain pathologies, including increased amyloid-beta (Aβ) and Tau hyperphosphorylation. Here, we aimed to determine whether HIV-1 infection causes AD-like pathologies in an HIV/AIDS humanized mouse model, and whether the CCR5 antagonist maraviroc alters HIV-induced pathologies.
Methods
NOD/scid–IL-2Rγcnull mice engrafted with human blood leukocytes were infected with HIV-1, left untreated or treated with maraviroc (120 mg/kg twice/day). Human cells in animal’s blood were quantified weekly by flow cytometry. Animals were sacrificed at week-3 post-infection; blood and tissues viral loads were quantified using p24 antigen ELISA, RNAscope, and qPCR. Human (HLA-DR+) cells, Aβ-42, phospho-Tau, neuronal markers (MAP 2, NeuN, neurofilament-L), gamma-secretase activating protein (GSAP), and blood-brain barrier (BBB) tight junction (TJ) proteins expression and transcription were quantified in brain tissues by immunohistochemistry, immunofluorescence, immunoblotting, and qPCR. Plasma Aβ-42, Aβ-42 cellular uptake, release and transendothelial transport were quantified by ELISA.
Results
HIV-1 significantly decreased human (h)CD4+ T-cells and hCD4/hCD8 ratios; decreased the expression of BBB TJ proteins claudin-5, ZO-1, ZO-2; and increased HLA-DR+ cells in brain tissues. Significantly, HIV-infected animals showed increased plasma and brain Aβ-42 and phospho-Tau (threonine181, threonine231, serine396, serine199), associated with transcriptional upregulation of GSAP, an enzyme that catalyzes Aβ formation, and loss of MAP 2, NeuN, and neurofilament-L. Maraviroc treatment significantly reduced blood and brain viral loads, prevented HIV-induced loss of neuronal markers and TJ proteins; decreased HLA-DR+ cells infiltration in brain tissues, significantly reduced HIV-induced increase in Aβ-42, GSAP, and phospho-Tau. Maraviroc also reduced Aβ retention and increased Aβ release in human macrophages; decreased the receptor for advanced glycation end products (RAGE) and increased low-density lipoprotein receptor–related protein-1 (LRP1) expression in human brain endothelial cells. Maraviroc induced Aβ transendothelial transport, which was blocked by LRP1 antagonist but not RAGE antagonist.
Conclusions
Maraviroc significantly reduced HIV-induced amyloidogenesis, GSAP, phospho-Tau, neurodegeneration, BBB alterations, and leukocytes infiltration into the CNS. Maraviroc increased cellular Aβ efflux and transendothelial Aβ transport via LRP1 pathways. Thus, therapeutically targeting CCR5 could reduce viremia, preserve the BBB and neurons, increased brain Aβ efflux, and reduce AD-like neuropathologies.”
This is what Dr J said Ed: Alzheimer’s and LL. I also think I think you have the right paper from 6/22. Both are mice related. The paper reports an intensely prosecuted mice study regarding CCR5/CCL5 presence and exclusion, and the memory results in test subject, mice.
Here’s Dr J from yesterday.
“And given the world's highest safety profile of Leronlimab to date, together with data from a recent preclinical study suggesting that blocking CCR5 in mice can rescue memory deficits, I believe a pilot study in Alzheimer's Disease is now justified.”
Investors Hangout: https://investorshangout.com/post/view?id=667...z8Tkf8UHFp
Here is a link to the paper you shared in case others want to read.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197199/
Ohm20 came with this paper from 11/21. Not the same, but also tested with Maravoric. Mainly going down the tech Tau/Amyloid path. I’ll share a few Maravoric citations from both later.
https://molecularneurodegeneration.biomedcent...21-00500-0
Here’s a couple of key passages from your 6/22 paper. They did a fairly exhaustive study. If they noticed a result in young mice, they tested it in old mice. If they noticed in CCR5 neg mice, they tested it in CCR5 knockout mice (Maravoric) Etc. Quite impressive results.
“Here, we report that a delayed (12-24h) increase in the expression of the C-C chemokine receptor type 5 (CCR5), an immune receptor well known as a co-receptor for HIV infection6,7, following the formation of a contextual memory, determines the duration of the temporal window for associating or linking that memory with subsequent memories.”
“CCR5 has been extensively studied in the context of inflammatory responses and HIV infection6,7. However, comparatively little is known about its role in learning and memory. Both CCR5 and its ligand CCL5 are highly enriched in the CA1 region of the hippocampus14–16, and CCR5 is a negative regulator of CREB activation and neuronal excitability15,17. Here, we demonstrate that a gradual increase in the expression of CCL5/CCR5 following memory formation closes the temporal window for memory linking, thus segregating memories that are temporally distinct.”
“To determine whether CCR5 modulates the temporal window for contextual memory linking1, we first exposed the mice to one context (context A) and either 5h, 1, 2 or 7 days later we exposed the mice to a second context (context
(Fig. 2a). Two days later, the mice were given an immediate shock in context B, and then contextual memory linking was tested 2d later in context A.” “During the contextual memory linking test, only the control group, but not the Opto-CCR5 group, showed evidence of memory linking (i.e., higher freezing in context A, that the mice experienced 5h before context B, compared to a novel context; Fig. 2e), confirming that increasing neuronal CCR5 activity specifically after exposure to context A is sufficient to impair contextual memory linking without impairing memory for context B.”
“Thus, two very different manipulations that decreased the levels of CCR5 (shRNA-mediated knockdown and a knockout) extended the temporal window for memory linking. Similar to Ccr5−/− mice, Ccl5 knockout (Ccl5−/−) mice also showed an extended linking window (Extended Data Fig. 6g), indicating that CCL5 is critical for CCR5 regulation of memory linking…Altogether, our results show that increasing or inhibiting CCR5 signaling impaired or extended (respectively) the temporal window for contextual memory linking, demonstrating a key role for CCR5 in setting the duration for the memory linking window.”
“This result supports the hypothesis that CCR5 activation excludes neurons from memory ensembles.”
“Altogether, the results presented suggest that the increase in CCR5 expression and signaling after learning prevents subsequent memories from being allocated to the neuronal ensemble encoding the initial memory, thus reducing the overlap between the two memory ensembles, and consequently attenuating memory linking.”
“CCR5 and CCL5 expression in peripheral immune cells increases with age31,32. Similar increases in aging neurons could contribute to age-related decreases in contextual memory linking1. To test this hypothesis, we measured hippocampal Ccr5 and Ccl5 expression in 16~18-month-old mice (middle-aged), an age in which mice still show intact contextual conditioning, but deficits in contextual memory linking”
“To test the effect of pharmacologically blocking CCR5 activity on contextual memory linking in middle-aged mice, maraviroc (an FDA approved CCR5 antagonist used for HIV treatment; Extended Data Fig. 4d–f)33 was infused to dCA1 of these mice 1h before they were exposed to context B in a contextual memory linking experiment with a 5h interval. Unlike control mice, maraviroc-treated mice showed memory linking (Fig. 4h). Thus, blocking CCR5 with maraviroc ameliorates the memory linking deficits in middle-aged mice. Altogether these results support a role for CCR5 expression in closing the temporal window for memory linking as well as in age-related deficits in memory linking.”
“In summary, the findings reported here show that a delayed (12-24h) increase in CCL5/CCR5 signaling in dCA1 neurons of a given memory ensemble closes the temporal window for memory linking. CCR5 activation decreases neuronal excitability, thus negatively regulating memory allocation. This change in memory allocation decreases the overlap between memory ensembles, and therefore impairs the ability of one memory to trigger the recall of the other, thus closing the temporal window for memory linking (Extended Data Fig. 10). Remarkably, our findings also show that an age-related increase in CCL5/CCR5 expression leads to impairments in memory linking in middle-aged mice that could be reversed with an FDA approved drug that inhibits this receptor, a result with significant clinical implications. All together the findings reported here provide the first insights into the molecular and cellular mechanisms that close the temporal window for memory linking, thus segregating the memories for events that are temporally distinct.”
Conclusion is just what Dr J said about resources.
“The challenge of course is that CytoDyn is just emerging from a two year clinical hold and doesn't have the resources to do everything we'd like. We're also keenly aware the need to stay focused and not try to do too much all at once.
But I believe we have this going forward, “Anything Maravoric can do, we can do better!” Like 100.83% better!
Running out of time for Ohms paper, but here’s a Maravoric citation from it.
“Abstract
Background
Neurocognitive impairment is present in 50% of HIV-infected individuals and is often associated with Alzheimer’s Disease (AD)-like brain pathologies, including increased amyloid-beta (Aβ) and Tau hyperphosphorylation. Here, we aimed to determine whether HIV-1 infection causes AD-like pathologies in an HIV/AIDS humanized mouse model, and whether the CCR5 antagonist maraviroc alters HIV-induced pathologies.
Methods
NOD/scid–IL-2Rγcnull mice engrafted with human blood leukocytes were infected with HIV-1, left untreated or treated with maraviroc (120 mg/kg twice/day). Human cells in animal’s blood were quantified weekly by flow cytometry. Animals were sacrificed at week-3 post-infection; blood and tissues viral loads were quantified using p24 antigen ELISA, RNAscope, and qPCR. Human (HLA-DR+) cells, Aβ-42, phospho-Tau, neuronal markers (MAP 2, NeuN, neurofilament-L), gamma-secretase activating protein (GSAP), and blood-brain barrier (BBB) tight junction (TJ) proteins expression and transcription were quantified in brain tissues by immunohistochemistry, immunofluorescence, immunoblotting, and qPCR. Plasma Aβ-42, Aβ-42 cellular uptake, release and transendothelial transport were quantified by ELISA.
Results
HIV-1 significantly decreased human (h)CD4+ T-cells and hCD4/hCD8 ratios; decreased the expression of BBB TJ proteins claudin-5, ZO-1, ZO-2; and increased HLA-DR+ cells in brain tissues. Significantly, HIV-infected animals showed increased plasma and brain Aβ-42 and phospho-Tau (threonine181, threonine231, serine396, serine199), associated with transcriptional upregulation of GSAP, an enzyme that catalyzes Aβ formation, and loss of MAP 2, NeuN, and neurofilament-L. Maraviroc treatment significantly reduced blood and brain viral loads, prevented HIV-induced loss of neuronal markers and TJ proteins; decreased HLA-DR+ cells infiltration in brain tissues, significantly reduced HIV-induced increase in Aβ-42, GSAP, and phospho-Tau. Maraviroc also reduced Aβ retention and increased Aβ release in human macrophages; decreased the receptor for advanced glycation end products (RAGE) and increased low-density lipoprotein receptor–related protein-1 (LRP1) expression in human brain endothelial cells. Maraviroc induced Aβ transendothelial transport, which was blocked by LRP1 antagonist but not RAGE antagonist.
Conclusions
Maraviroc significantly reduced HIV-induced amyloidogenesis, GSAP, phospho-Tau, neurodegeneration, BBB alterations, and leukocytes infiltration into the CNS. Maraviroc increased cellular Aβ efflux and transendothelial Aβ transport via LRP1 pathways. Thus, therapeutically targeting CCR5 could reduce viremia, preserve the BBB and neurons, increased brain Aβ efflux, and reduce AD-like neuropathologies.”
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