Plotinus, you have drawn a connection the published literature now supports with more precision than most readers of either paper would recognize immediately.
The Cu(ATSM) paper describes a repair mechanism for a cascade whose initiation the CCR5 literature now independently documents. The sequence is worth walking through carefully because the two papers describe different ends of the same pathological chain.
Vascular dysfunction at the blood-brain barrier precedes and drives the microglial recruitment and P-glycoprotein failure the Monash group works to repair with copper. The clearance of proteins depends partly on the permeation of the blood-brain barrier and on the exchange of water and soluble contents between cerebrospinal fluid and interstitial fluid, and when that exchange fails, amyloid-beta accumulates not because the brain produces more of it but because the drain is blocked.
The Cu(ATSM) compound repairs the P-gp pump at the BBB endothelium, restoring efflux transport and allowing amyloid clearance to resume. That is a downstream repair strategy targeting the consequence of vascular architectural failure.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8674693/table/T3
What CCR5 blockade addresses is upstream of that failure point. Inflammation and complement activation induce microglia to transition into a pro-inflammatory state, releasing cytokines and chemokines which participate in multiple signaling pathways, including the CCR5-GPCR-Ras-MAPK pathway. CCR5 is directly named in the neuroinflammatory signaling cascade at the BBB.
The activated microglia recruited to the inflamed vascular wall are not simply responding to amyloid plaques; they are amplifying BBB permeability through the same proinflammatory mediator release and reactive oxygen species generation which degrades tight junction proteins and impairs P-gp function in the first place. Activated microglia can increase BBB permeability and vascular leakage through the release of proinflammatory mediators and generation of reactive oxygen species, promoting the recruitment of additional monocytes and CD8+ T cells from peripheral blood into the CNS compartment. Cancer
https://www.cancernetwork.com/view/fda-holds-...5-mss-mcrc
https://www.targetedonc.com/view/leronlimab-g...-crc-trial
The architecture is a self-amplifying loop: vascular inflammation recruits CCR5-bearing myeloid cells to the BBB, those cells release mediators that further degrade BBB integrity, degraded BBB integrity allows peripheral immune cells to enter the CNS compartment, and the resulting neuroinflammatory environment impairs P-gp function and traps amyloid-beta inside the brain. Cu(ATSM) enters this loop at the P-gp repair point and restores efflux capacity. Leronlimab enters this loop at the CCR5-mediated myeloid recruitment point and attenuates the inflammatory amplification driving BBB degradation upstream of P-gp failure.
These are not competing mechanisms. They are addressing the same pathological cascade from opposite ends. The Monash group's finding that Cu(ATSM) may also enhance microglial capacity to consume and break down amyloid plaques more effectively adds a third layer: a repaired BBB with restored P-gp function, combined with attenuated CCR5-driven neuroinflammation allowing microglia to return to their homeostatic surveillance and clearance function rather than their activated destructive state, and microglia with restored phagocytic capacity clearing the amyloid burden that accumulated during the inflammatory period. Each mechanism complements rather than substitutes for the others.
What SALIENT-AD measures with microglial PET imaging at Weill Cornell is precisely the inflammatory activation state of the microglia before and after leronlimab treatment. The PET tracer quantifies microglial activation rather than amyloid burden directly, which means the trial measures the upstream CCR5-dependent neuroinflammatory component rather than the downstream amyloid clearance consequence.
The Cu(ATSM) paper suggests the downstream amyloid clearance consequence of reducing that upstream microglial activation may be measurable and significant. Whether SALIENT-AD's primary endpoint design captures that amyloid consequence directly depends on the secondary endpoint architecture of the trial.
The dots you connect are real, and the published literature is now dense enough such that the connections can be made with precision rather than via analogy.
The Cu(ATSM) paper describes a repair mechanism for a cascade whose initiation the CCR5 literature now independently documents. The sequence is worth walking through carefully because the two papers describe different ends of the same pathological chain.
Vascular dysfunction at the blood-brain barrier precedes and drives the microglial recruitment and P-glycoprotein failure the Monash group works to repair with copper. The clearance of proteins depends partly on the permeation of the blood-brain barrier and on the exchange of water and soluble contents between cerebrospinal fluid and interstitial fluid, and when that exchange fails, amyloid-beta accumulates not because the brain produces more of it but because the drain is blocked.
The Cu(ATSM) compound repairs the P-gp pump at the BBB endothelium, restoring efflux transport and allowing amyloid clearance to resume. That is a downstream repair strategy targeting the consequence of vascular architectural failure.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8674693/table/T3
What CCR5 blockade addresses is upstream of that failure point. Inflammation and complement activation induce microglia to transition into a pro-inflammatory state, releasing cytokines and chemokines which participate in multiple signaling pathways, including the CCR5-GPCR-Ras-MAPK pathway. CCR5 is directly named in the neuroinflammatory signaling cascade at the BBB.
The activated microglia recruited to the inflamed vascular wall are not simply responding to amyloid plaques; they are amplifying BBB permeability through the same proinflammatory mediator release and reactive oxygen species generation which degrades tight junction proteins and impairs P-gp function in the first place. Activated microglia can increase BBB permeability and vascular leakage through the release of proinflammatory mediators and generation of reactive oxygen species, promoting the recruitment of additional monocytes and CD8+ T cells from peripheral blood into the CNS compartment. Cancer
https://www.cancernetwork.com/view/fda-holds-...5-mss-mcrc
https://www.targetedonc.com/view/leronlimab-g...-crc-trial
The architecture is a self-amplifying loop: vascular inflammation recruits CCR5-bearing myeloid cells to the BBB, those cells release mediators that further degrade BBB integrity, degraded BBB integrity allows peripheral immune cells to enter the CNS compartment, and the resulting neuroinflammatory environment impairs P-gp function and traps amyloid-beta inside the brain. Cu(ATSM) enters this loop at the P-gp repair point and restores efflux capacity. Leronlimab enters this loop at the CCR5-mediated myeloid recruitment point and attenuates the inflammatory amplification driving BBB degradation upstream of P-gp failure.
These are not competing mechanisms. They are addressing the same pathological cascade from opposite ends. The Monash group's finding that Cu(ATSM) may also enhance microglial capacity to consume and break down amyloid plaques more effectively adds a third layer: a repaired BBB with restored P-gp function, combined with attenuated CCR5-driven neuroinflammation allowing microglia to return to their homeostatic surveillance and clearance function rather than their activated destructive state, and microglia with restored phagocytic capacity clearing the amyloid burden that accumulated during the inflammatory period. Each mechanism complements rather than substitutes for the others.
What SALIENT-AD measures with microglial PET imaging at Weill Cornell is precisely the inflammatory activation state of the microglia before and after leronlimab treatment. The PET tracer quantifies microglial activation rather than amyloid burden directly, which means the trial measures the upstream CCR5-dependent neuroinflammatory component rather than the downstream amyloid clearance consequence.
The Cu(ATSM) paper suggests the downstream amyloid clearance consequence of reducing that upstream microglial activation may be measurable and significant. Whether SALIENT-AD's primary endpoint design captures that amyloid consequence directly depends on the secondary endpoint architecture of the trial.
The dots you connect are real, and the published literature is now dense enough such that the connections can be made with precision rather than via analogy.
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