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Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α -synuclein aggregates in neurodegenerative diseases. However, due to the complex structure and ambiguous pathogenic species of the misfolded proteins, a universal approach to remove the misfolded proteins remains unavailable. Here, we found that a polyphenol, α -mangostin, reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation, which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins. Nanoformulation of α -mangostin efficiently delivered α -mangostin to microglia, relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia, which thus impressively relieved the neuropathological changes in both Alzheimer's disease and Parkinson's disease model mice. These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming, and demonstrate nanoformulated α -mangostin as a potential and universal therapy against neurodegenerative diseases. NP- α -M rejuvenates microglial surveillance of misfolded proteins through metabolic reprogramming, which provides a universal approach to clear multiple misfolded proteins and treat neurodegenerative diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights • A multifunctional metal chelator with AChE inhibition improves Cu(II)-induced dementia. • It attenuates Cu(II)-induced dendritic damage in the hippocampus. • It inhibits Cu(II)-induced inflammatory responses in the hippocampus. • It attenuates Cu(II)-induced oxido-nitrosative stress in the hippocampus. • These effects could be associated with Cu(II)-chelation against AChE-inhibition. Abstract Excess copper exposure is a risk factor of neurodegeneration related to Alzheimer's disease (AD). Evidence indicates that, besides promoting amyloid β aggregation, activation of neuroinflammation and oxido-nitrosative stress (two key pathophysiological processes of AD) may also play important roles in Cu(II)-induced neuronal injury. Therefore, the copper-chelating strategy has gained attention in search for new anti-AD drugs. We previously reported a novel multifunctional compound N1 , N2 -bis(3-(S)-meptazinol-propyl) oxalamide (ZLA), a bis-(−)-nor-meptazinol-oxalamide hybrid with properties of dual binding site acetylcholinesterase (AChE) inhibition and Cu(II)/Zn(II) chelation. The present study was aimed to explore its effect on cognitive deficits caused by intrahippocampal injection of Cu(II) in mice. Results showed that ZLA (2, 5 mg/kg; i.p.) treatment significantly ameliorated the Cu(II)-induced impairment of hippocampus-dependent learning and memory, whereas rivastigmine, an AChE inhibitor showing a similar potency of enzyme inhibition to ZLA, had no obvious effect. Immunohistochemical and Western blot analyses revealed that ZLA attenuated the decrease in hippocampal expression of microtubule-associated protein 2 (MAP2, a dendritic marker) in Cu(II)-challenged mice. Further analysis showed that ZLA suppressed the Cu(II)-evoked microglial activation. Moreover, it inhibited the Cu(II)-evoked production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β and expression of inducible nitric oxide synthase in the hippocampus. The Cu(II)-induced oxidative and nitrosative stress in the hippocampus was also attenuated after ZLA treatment. Collectively, these results suggest that ZLA ameliorates the Cu(II)-caused cognitive deficits. Inhibition of neuroinflammation and oxido-nitrosative stress, and thus ameliorating neuronal injury, may be the potential mechanism for the anti-amnesic effect of ZLA. [ABSTRACT FROM AUTHOR]

Copper dyshomeostasis is involved in the pathogenesis of Alzheimer's disease (AD). Microglia play a major role in the proteolytic clearance of oligomeric β-amyloid (Aβo). Here, we investigated whether Cu(II) affects microglial Aβo clearance and whether this effect involves autophagy-lysosomal pathway. Microtubule associated protein 1 light chain 3 (LC3)-II and p62 protein levels and autophagic flux in Cu(II)-treated microglia were detected. Aβo clearance was detected by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence. In vivo , Cu(II) and Aβo were injected into mouse hippocampus to evaluate Aβ clearance. The results showed that Cu(II) inhibited phagocytic uptake and intracellular degradation of Aβo in microglial cultures. Additionally, Cu(II) elevated LC3-II and p62 protein levels and impaired autophagic flux. It also inhibited transcription factor EB (TFEB) expression and lysosomal biogenesis. Moreover, Cu(II) activated mammalian target of rapamycin kinase (mTOR), an upstream signaling of TFEB. The mTOR inhibitor PP242 ameliorated Cu(II)-impaired TFEB expression, lysosomal biogenesis, autophagic flux, and Aβo clearance in microglia. In vivo , Cu(II) inhibited microglial Aβo clearance in mouse hippocampus, an effect accompanied with activation of mTOR and impairment of TFEB expression and lysosomal biogenesis. Collectively, our results suggest that Cu(II) reduces microglial Aβo clearance through disrupting lysosomal biogenesis and autophagic flux. This effect could involve modulation of mTOR-TFEB axis and was prevented by pharmacological antagonism of mTOR. This study reveals a novel mechanism for Cu(II) involvement in AD. Our results implicate that rescue of Cu(II)-impaired autophagy-mediated lysosomal degradation may provide a new strategy to benefit multiple neurodegenerative disorders. • Cu(II) impairs oligomeric Aβ clearance in microglia in vitro and in vivo. • Cu(II) inhibits autophagic flux and lysosomal biogenesis in microglia. • Cu(II) modulates mTOR-TFEB signaling axis. • Cu(II) impairs microglial Aβ clearance via disrupting autophagy-lysosomal pathway. [ABSTRACT FROM AUTHOR]