An “Amyloid‐β Cleaner” for the Treatment of Alzheimer's Disease by Normalizing Microglial Dysfunction

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive and memory loss. The vicious circle between dysfunctional microglia and amyloid‐β (Aβ) is a crucial pathological event and accelerates the progression of AD. Herein, a zwitterionic poly(carboxybetaine) (PCB)‐based nanoparticle (MCPZFS NP) with normalizing the dysfunctional microglia and Aβ recruitment is established for the treatment of AD. Compared with the neural polyethylene glycol (PEG)‐based nanoparticles (MEPZFS NPs), the MCPZFS NPs significantly alleviate the priming of microglia by decreasing the level of proinflammatory mediators and promoting the secretion of BDNF. Most importantly, quite different from PEG, the PCB‐based NPs exhibit the behavior to recruit Aβ into microglia, which significantly enhances the Aβ phagocytosis. Moreover, the Aβ degradation is changed from the conventional lysosomal/autophagy to the proteasomal pathway in the presence of MCPZFS NPs. After the treatment with MCPZFS NPs, the Aβ burden, neuron damages, memory deficits, and neuroinflammation of APPswe/PS1dE9 mice are significantly attenuated in the brain. Therefore, the PCB‐based MCPZFS NPs have great potential to serve as an “Aβ cleaner” and provide a new insight into the therapeutic strategy for AD therapy.

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“…The mice were placed individually in the pool facing the pool wall. The ratio of the time in the original quadrant of the total time was recorded, and the number of times that the rat crossed the original platform in 90 s was measured [ 50 ].…”

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“…Nanoparticle-based AD treatment has been explored recently in the literature. Liu et al reported on AD treatment application by zwitterionic poly(carboxybetaine) (PCB)-based nanoparticles coloaded with fingolimod, siSTAT3, and zinc oxide, henceforth named MCPZFS nanoparticles or MCPZFS NPs [ 185 ]. The diameter of the MCPZF NPs was between 84.0 and 89.4 nm.…”

“…The diameter of the MCPZF NPs was between 84.0 and 89.4 nm. A mannose analog 4-aminophenyl α-d-mannopyranoside (Man) was added to the nanoparticles to facilitate BBB penetration and improve the targeting of microglia [ 185 ]. MCPZFS nanoparticles significantly improve microglial priming by reducing the level of proinflammatory mediators and promoting the secretion of brain-derived neurotrophic factor (Fig.…”

“…MCPZFS nanoparticles significantly improve microglial priming by reducing the level of proinflammatory mediators and promoting the secretion of brain-derived neurotrophic factor (Fig. 8 ) [ 185 ]. Importantly, MCPZFS nanoparticles increase Aβ recruitment into microglia, which substantially enhances Aβ phagocytosis, and Aβ degradation is changed from the conventional lysosomal/autophagy pathway to the proteasomal pathway in the presence of MCPZFS nanoparticles [ 185 ].…”

“…8 ) [ 185 ]. Importantly, MCPZFS nanoparticles increase Aβ recruitment into microglia, which substantially enhances Aβ phagocytosis, and Aβ degradation is changed from the conventional lysosomal/autophagy pathway to the proteasomal pathway in the presence of MCPZFS nanoparticles [ 185 ]. This system elevated numerous key proinflammatory cytokines, such as interleukin 1-β (IL-1β), IFN-γ, IL-6, and interleukin 17A, in the brains of APP or presenilin 1-transgenic mice.…”