Amyloid-β oligomer-induced neurotoxicity by exosomal interactions between neuron and microglia
Man Kit Tong1, Abhimanyu Thakur2, Tian Yang1
1Department of Neurosciences, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, China.
Abstract:
A hallmark of Alzheimer's disease (AD) is amyloid-β (Aβ) plaque deposition in the brain, causing deficits in cognitive function. Amyloid-beta oligomers (AβOs), the soluble precursor peptides producing Aβ plaques, also produce neurotoxicity and microgliosis together with glycolytic reprogramming. Recently, monocarboxylate transporter 1 (MCT1), a key glycolysis regulator, and its ancillary protein, CD147, are found to play an important role in the secretion of exosomes, 30-200 nm vesicles in size, which are considered as toxic molecule carriers in AD. However, the effect of low-concentration AβOs (1 nM) on microglia MCT1 and CD147 expression as well as 1 nM AβOs-treated microglia-derived exosomes on neuronal toxicity remain largely elusive. In this study, 1 nM AβOs induce significant axonopathy and microgliosis. Furthermore, 1 nM AβOs-treated neurons- or microglia-derived exosomes produce axonopathy through their autologous or heterologous uptake by neurons, supporting the role of exosomes as neurotoxicity mediators in AD. Interestingly, MCT1 and CD147 are enhanced in microglia by treatment with 1 nM AβOs or exosomes from 1 nM AβOs-treated- microglia or neurons, suggesting the implication of AβOs-induced enhanced MCT1 and CD147 in microglia with AD neuropathogenesis, which is consistent with the in-silico analysis of the single cell RNA sequencing data from microglia in mouse models of AD and AD patients.
Insights
Low-concentration amyloid-beta oligomers (AβOs) cause microgliosis and axonopathy. Exosomes from AβO-treated cells mediate neurotoxicity, with enhanced microglia monocarboxylate transporter 1 (MCT1) and CD147 implicated in Alzheimer's disease (AD) neuropathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques, leading to cognitive decline.
- Amyloid-beta oligomers (AβOs) cause neurotoxicity and microgliosis, impacting cellular metabolism.
- Monocarboxylate transporter 1 (MCT1) and CD147 are involved in exosome secretion and may play a role in AD.
Purpose of the Study:
- To investigate the effects of low-concentration AβOs (1 nM) on microglia MCT1 and CD147 expression.
- To determine the neurotoxicity of exosomes derived from AβO-treated microglia.
- To elucidate the role of MCT1 and CD147 in AβO-induced neuropathogenesis in AD.
Main Methods:
- Treatment of microglia and neurons with 1 nM AβOs.
- Analysis of exosome-mediated neurotoxicity via autologous and heterologous uptake.
- Assessment of MCT1 and CD147 expression in microglia.
- In-silico analysis of single-cell RNA sequencing data from AD models.
Main Results:
- 1 nM AβOs induced significant axonopathy and microgliosis.
- Exosomes from 1 nM AβO-treated cells caused axonopathy upon neuronal uptake.
- Microglial MCT1 and CD147 expression were enhanced by 1 nM AβOs and derived exosomes.
- Findings were consistent with in-silico analysis of AD microglia data.
Conclusions:
- Exosomes act as neurotoxicity mediators in AD, carrying toxic molecules.
- Enhanced MCT1 and CD147 in microglia are implicated in AβO-induced AD neuropathogenesis.
- This study highlights a novel mechanism of AD pathogenesis involving exosomes and microglial metabolic reprogramming.
