Age-related macular degeneration (AMD) is characterized by the accumulation of debris in the posterior eye. In this study we evaluated peripheral blood monocyte phagocytic function at various stages of AMD and in aged matched control participants. Real-time tri-color flow cytometry was used to quantify phagocytic function of peripheral blood monocyte subsets (non-classic, intermediate and classic) isolated from subjects with intermediate or late AMD and compared with age matched healthy controls. Assessment of phagocytic function of monocytes isolated from those with and without reticular pseudodrusen was also made, and the effect of glatiramer acetate on phagocytic function assessed. Phagocytic function was reduced in all subjects with AMD, irrespective of stage of disease. However, there was no correlation between phagocytic function and drusen load, nor any difference between the level of phagocytosis in those with or without reticular pseudodrusen. Treatment with glatiramer acetate increased phagocytosis of classical and non-classical monocytes, normalizing the reduction in phagocytosis observed in those with AMD. These findings suggest that defective systemic phagocytosis is associated with both intermediate and late stages of AMD, highlighting a potential role in the accumulation of debris that occurs early in the disease process. Assessing peripheral monocyte phagocytic function provides further insights into the etiology of this disease and offer a novel therapeutic target.

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Introduction: Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions. Methods: In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses. Results: We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance. A proposed panel including four leukocyte markers -CD11c, CD59, CD91, and CD163 -predicts patients' PET Aβ status with an area under the curve (AUC) of 0.93 (0.88 to This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Background: We and others have reported that glatiramer acetate promotes innate phagocytosis. Methods: In this study, we investigated the interaction between glatiramer acetate and amyloid-β (Aβ) by using circular dichroism and microscale thermophoresis. Glatiramer acetate was delivered intracerebroventricularly to 22-month-old APP/PS1 mice by using mini-osmotic pumps. Mice underwent behavioural testing for two consecutive weeks after three-weeks treatment. Five weeks after implantation, animals were sacrificed and brain samples were collected for electrophysiology, immunochemistry and histopathology studies. Intracerebroventricular delivery of glatiramer acetate to sheep was also examined. Results: Glatiramer acetate binds to amyloid-β within high affinity and antagonize its toxicity. Glatiramer acetate treatment significantly improved cognitive function, restored long-term potentiation, reduced soluble amyloid-β and amyloid-β plaques in aged APP/PS1 mice, and promoted energy metabolism in sheep. Conclusions: Our results suggest a novel treatment strategy that targets both innate phagocytosis and amyloid-β, which may prove useful for treatment of all stages of Alzheimer’s disease.

Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques in the brain, leading to neuroinflammation, synaptic dysfunction and cognitive decline. Developing therapeutic strategies that enhance Aβ clearance is an active area of research. Methods: In this study, we investigated glatiramer acetate (GA) that has demonstrated the ability to promote Aβ phagocytosis by mouse microglia. Through a series of experiments, we aimed to understand the underlying mechanisms and their implications for AD pathogenesis. First, the interaction between GA and Aβ was investigated using circular dichroism and microscale thermophoresis. Second, the reduction of Aβ-mediated toxicity and attenuation of neuroinflammation were investigated using MTT assay, membrane fluidity assay and long-term potentiation (LTP). Third, the long-term therapeutic effect was investigated by directly delivering GA into lateral cerebral ventricles of 22-month-old APP/PS1 mice and evaluating with behavioural tests, LTP, ELISA and IHC. Finally, biosafety and pharmacokinetics were investigated in sheep. Results: Our findings suggest that the binding between GA and Aβ contributes to the reduction of Aβ-mediated toxicity. Additionally, by enhancing Aβ clearance and attenuating microglial activation, GA creates an environment more conducive to synaptic plasticity and the restoration of long-term potentiation (LTP), contributing to the improvement of cognitive function and behavioural deficits observed in mouse model of AD. Conclusions: Overall, these results highlight the potential of the phagocytosis-promoting drugs to enhance Aβ clearance and its therapeutic implications for AD.