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  • Discussion The present experiments follow up and are complet

    2024-02-22

    Discussion The present experiments follow-up and are completely consistent with our prior findings [26] that blood Aβ is subject to peripheral clearance by a major pathway for circulating pathogens in primates, immune adherence [30,31]. CR1-mediated erythrocyte immune adherence, as well as CR1-mediated macrophage capture of pathogens, requires complement activation and opsonization. Although some pathogens, including Aβ [26–29], can, by themselves, stimulate complement activation and opsonization through binding of the pathogen to C1q, these processes are markedly enhanced when the pathogens form ICs, which bind with higher affinity to C1q. Thus, in the present experiments, the formation of Aβ ICs, as would occur with active and passive Aβ immunotherapy, increased Aβ activation of fluid phase complement by as much as 34-fold. This enhancement was predictably followed by multifold increases in complement opsonization, erythrocyte adherence, and macrophage phagocytosis. In vivo, capture of Aβ through the erythrocyte clearance pathway was also robustly increased for Aβ ICs compared with Aβ. Whether generated in the blood by active immunization or infused into the blood by passive immunization, Aβ Triflusal are, first and foremost, directly exposed to circulating Aβ, permitting the formation of Aβ ICs. Theoretically, there is, in fact, enough Aβ in the plasma compartment to form ICs with all the bapineuzumab infused into the average human being after a typical 1 mg/kg dose (assuming an average body weight and blood volume of 80.7 kg and 4.7 L, respectively, and an average plasma Aβ level of 500 pg/mL [32,33,36,37]). Although, in practice, antibodies do not bind antigens with 100% efficiency (the KD for bapineuzumab is reported to be 89 nM for soluble Aβ40 [38]), the amount of Aβ antibody available to enter the brain should still be substantially limited by formation of Aβ ICs in the blood and their subsequent clearance by the mechanisms studied in this report. Antibodies surviving these processes would then also have to penetrate the blood-brain barrier. It may not be surprising, therefore, that the concentrations of Aβ antibodies that reach the brain are estimated to be <0.1% of the amount administered peripherally and many orders of magnitude less than the molar amount of Aβ present in the AD brain [12–14]. Data on plasma Aβ levels after Aβ immunotherapy [reviewed in [39]] and after experimental infusion of Aβ antibodies in AD transgenic mice [9,11] have been reported in some cases. Although these studies typically find increased plasma Aβ after treatment, they do not Triflusal necessarily contradict the present results and, in fact, may support them. Efflux of CNS Aβ into the plasma compartment after treatment appears to be rapid and extensive and, after treatment, virtually all of the Aβ in plasma appears to be in the form of Aβ ICs [9]. However, if these high levels of Aβ ICs were simply “sequestered” in the circulation, as presently assumed, they would almost certainly lead to immune complex disorders, where high levels of uncleared ICs lodge in various organs and cause significant pathology (reviewed in [40]). Subsequent infusions of Aβ antibody, as in AD immunotherapy, would further compound this problem. Thus, the data on increased plasma Aβ after treatment with Aβ antibodies actually demand an active peripheral clearance mechanism such as immune adherence to avoid immune complex disease in the recipients. The Aβ ICs cannot simply persist and build up. A more accurate representation would therefore be that the enhanced efflux of CNS Aβ into the plasma seen after Aβ infusion is interactive with the enhanced clearance of peripheral Aβ shown in the present experiments. AD immunotherapy studies on plasma alone do not (and cannot) measure this latter contribution, whereas our experiments, using infusions of Aβ ICs (as opposed to only the antibodies themselves) do so. Although it is unquestionable that AD is a CNS disease, there is ample precedent for peripheral influences on brain disorders (e.g., effects of diabetes on the CNS) (reviewed in [41]). Whether considered in light of the “peripheral sink hypothesis” [9–11] or some other mechanism [34], impaired peripheral clearance of Aβ, as shown for AD subjects in our previous research [26], could not be favorable for brain concentrations of Aβ, whereas enhanced peripheral clearance by Aβ antibodies, as shown by the present data, should be beneficial. Accordingly, whether or not the Aβ antibodies provided by Aβ immunotherapy actually penetrate to the brain in sufficient amounts to assist removal of brain Aβ, the peripheral effects of such antibodies should not be ignored. Likewise, whether or not normal erythrocyte and macrophage peripheral clearance pathways are sufficient to deal with the increased plasma Aβ brought about by AD immunotherapy [39], approaches to enhance peripheral, complement-mediated removal of circulating pathogens have been reported and might be considered for Aβ. For example, a bispecific antibody that bound both the pathogen and the erythrocyte receptor for complement-opsonized complexes, CR1, has been shown to substantially enhance clearance of the pathogen [35].