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Posted On: 12/19/2023 10:13:04 AM
Post# of 148870
NSAID’s, also aspirin, acetaminophen and COX inhibitors like Celecoxib inhibit prostaglandins via the COX pathway. CCR5 blocking as we are aware is a fundamentally different mechanism of action which touches on immune cell trafficking and impacts microglial cells.
My intuition is that the background inflammation may challenge the capacity of the brain to remove any byproducts from that activity through the glymphatic system which act in a fluid/waste drainage capacity. I have to imagine the propensity to develop tau and the tangles and malformed proteins which are the observable hallmarks of AD and the target of many failed drug trials, is enhanced under conditions which impede this drainage. For example, the brain shrinks slightly during sleep, allowing the glymphatic system to operate more efficiently and “take out the trash” if you will. There is some healthy synaptic pruning going on at the same time during sleep…not all memory is useful to store, some of my grade-school test scores for example. Chronic sleep disruption is a known risk factor for AD. CCR5 blockade should tamp down microglial activity, which exacerbates tau pathology and contributes to synaptic loss. The inflammatory cytokines are injurious to a subset of cells in the brain, neurons and astrocyte’s among them. The main point being that at a high level CCR5 involves a vastly different mechanism of action than NSAID’s and other anti-inflammatory drugs. CCL5 left unchecked will allow damage levels over time which are going to allow abnormal protein deposition, an unhealthy level of synaptic pruning it took us decades to build up, and make it more challenging for the glymphatic system to keep up. CCR5 blockade is like the fire brigade showing up and saving the whole house from becoming engulfed…maybe you just lose the garage which can be re-built.
We are far away from AD trial’s with Leronlimab but I wonder if in initial trials you can simply go after functional outcomes that are more important and less expensive than MRI’s looking for plaque, the removal of which in drug trials that received approval had marginal or no impact on actual brain function. I can’t overstate my bias here that going after plaque is misdirected, it is the result of other processes at work and you have to look further upstream to the real triggers. It’s dangerous to be over simplistic, there are genetic factors at work here also, I just think BP is barking up the wrong tree with the focus on tau.
My intuition is that the background inflammation may challenge the capacity of the brain to remove any byproducts from that activity through the glymphatic system which act in a fluid/waste drainage capacity. I have to imagine the propensity to develop tau and the tangles and malformed proteins which are the observable hallmarks of AD and the target of many failed drug trials, is enhanced under conditions which impede this drainage. For example, the brain shrinks slightly during sleep, allowing the glymphatic system to operate more efficiently and “take out the trash” if you will. There is some healthy synaptic pruning going on at the same time during sleep…not all memory is useful to store, some of my grade-school test scores for example. Chronic sleep disruption is a known risk factor for AD. CCR5 blockade should tamp down microglial activity, which exacerbates tau pathology and contributes to synaptic loss. The inflammatory cytokines are injurious to a subset of cells in the brain, neurons and astrocyte’s among them. The main point being that at a high level CCR5 involves a vastly different mechanism of action than NSAID’s and other anti-inflammatory drugs. CCL5 left unchecked will allow damage levels over time which are going to allow abnormal protein deposition, an unhealthy level of synaptic pruning it took us decades to build up, and make it more challenging for the glymphatic system to keep up. CCR5 blockade is like the fire brigade showing up and saving the whole house from becoming engulfed…maybe you just lose the garage which can be re-built.
We are far away from AD trial’s with Leronlimab but I wonder if in initial trials you can simply go after functional outcomes that are more important and less expensive than MRI’s looking for plaque, the removal of which in drug trials that received approval had marginal or no impact on actual brain function. I can’t overstate my bias here that going after plaque is misdirected, it is the result of other processes at work and you have to look further upstream to the real triggers. It’s dangerous to be over simplistic, there are genetic factors at work here also, I just think BP is barking up the wrong tree with the focus on tau.
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