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Posted On: 06/11/2024 2:58:01 AM
Post# of 148870
Re: chazzledazzle #144341
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A good CCR5 antagonists may pair well with these approved or soon approved AD drugs to provide a much better outcome.
From a business standpoint partnering might be a good decision. From a scientific standpoint it's awful. Pairing up with drugs that have bad side effects when leronlimab would do the same thing as those drugs and more doesn't make sense.
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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. CCR5 antagonist reduces HIV-induced amyloidogenesis, tau pathology, neurodegeneration, and blood-brain barrier alterations in HIV-infected hu-PBL-NSG mice
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We found that the microglial-derived CCL-3/-4/-5 bind and activate neuronal CCR5, which in turn promotes mTORC1 activation and disrupts autophagy and aggregate-prone protein clearance. CCR5 and its cognate chemokines are upregulated in the brains of pre-manifesting mouse models for Huntington’s disease (HD) and tauopathy, suggesting a pathological role of this microglia-neuronal axis in the early phases of these diseases. CCR5 upregulation is self-sustaining, as CCL5-CCR5 autophagy inhibition impairs CCR5 degradation itself. Finally, pharmacological or genetic inhibition of CCR5 rescues mTORC1 hyperactivation and autophagy dysfunction, which ameliorates HD and tau pathologies in mouse models.
Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration
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However, oral administration of a low dose of maraviroc protected glia limitans partially, maintained the integrity of endothelial monolayer, reduced the infiltration of T cells, attenuated neuroinflammation, and decreased α-synucleinopathy in the SN. Low-Dose Maraviroc, an Antiretroviral Drug, Attenuates the Infiltration of T Cells into the Central Nervous System and Protects the Nigrostriatum in Hemiparkinsonian Monkeys
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