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Published on: October 18, 2016
Folate Deficiency Increased Microglial Amyloid-β Phagocytosis via the RAGE Receptor in Chronic Unpredictable
Junting Fan1,2, Zewei Ma1,2, Yunqin Zheng1,2
1Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
Abstract:
Depression is often considered one of the prevalent neuropsychiatric symptoms of Alzheimer's disease (AD). β-amyloid (Aβ) metabolism disorders and impaired microglia phagocytosis are potential pathological mechanisms between depression and AD. Folate deficiency (FD) is a risk factor for depression and AD. In this study, we used a chronic unpredictable mild stress (CUMS) rat model and a model of Aβ phagocytosis by BV2 cells to explore the potential mechanisms by which FD affects depression and AD. The results revealed that FD exacerbated depressive behavior and activated microglia in CUMS rats, leading to an increase in intracellular Aβ and phagocytosis-related receptors for advanced glycation end products (RAGE). Then, in vitro results showed that the expression of the RAGE receptor and M2 phenotype marker (CD206) were upregulated by FD treatment in BV2 cells, leading to an increase in Aβ phagocytosis. However, there was no significant difference in the expression of toll-like receptor 4 (TLR4) and clathrin heavy chain (CHC). Furthermore, when using the RAGE-specific inhibitor FPS-ZM1, there was no significant difference in Aβ uptake between folate-normal (FN) and FD BV2 cell groups. In conclusion, these findings suggest FD may promote microglia phagocytosis Aβ via regulating the expression of RAGE or microglia phenotype under Aβ treatment.
Insights
Folate deficiency worsens depression and Alzheimer's disease (AD) symptoms by affecting microglia. This study reveals folate deficiency promotes Aβ clearance via RAGE regulation in microglia.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Depression is a common neuropsychiatric symptom in Alzheimer's disease (AD).
- Impaired beta-amyloid (Aβ) metabolism and microglia phagocytosis are implicated in AD and depression.
- Folate deficiency (FD) is a known risk factor for both depression and AD.
Purpose of the Study:
- To investigate the mechanisms by which folate deficiency (FD) influences depression and Alzheimer's disease (AD).
- To explore the role of microglia phagocytosis and specific receptors in the context of FD, depression, and AD.
Main Methods:
- Utilized a chronic unpredictable mild stress (CUMS) rat model to assess depressive behavior and microglial activation.
- Employed an in vitro BV2 cell model to study Aβ phagocytosis under folate-deficient conditions.
- Investigated the expression of receptors like RAGE, TLR4, and CHC, and used a RAGE-specific inhibitor (FPS-ZM1).
Main Results:
- FD exacerbated depressive behavior and activated microglia in CUMS rats, increasing intracellular Aβ and RAGE expression.
- In vitro, FD upregulated RAGE and M2 marker CD206 in BV2 cells, enhancing Aβ phagocytosis.
- Inhibition of RAGE abolished differences in Aβ uptake between folate-normal and folate-deficient cells.
Conclusions:
- Folate deficiency may promote Aβ phagocytosis by microglia.
- This process appears to be mediated through the regulation of RAGE expression or microglia phenotype.
- Findings suggest a potential therapeutic target for managing depression and AD comorbidities related to folate deficiency.
