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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 …