Effects of Microglial Cytokines on Alzheimer’s Disease-Related Phenomena

Yan, Jing; Wang, Xiaowan; Kalicki, Colin; Menta, Blaise; Baumgardner, Megan; Koppel, Scott J.; Weidling, Ian; Perez-Ortiz, Judit; Wilkins, Heather; Swerdlow, Russell H.

doi:10.3233/jad-180820

Cited by 10 publications

(7 citation statements)

References 58 publications

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“…Previous reports on LD aggregation in neurons are scarce. Ji et al reported a decrease in LD aggregation in SH-SY5Y cells following the incubation with BV2 cell line supernatant [29], which is inconsistent with our ndings. We speculate that this discrepancy may stem from variations in experimental conditions, culture systems, such as the source and passage of cell lines, or differences in LPS processing method.…”

Section: Discussioncontrasting

confidence: 99%

Regulation of neuronal lipid droplet aggregation by microglia through the lactate-lysosome signaling pathway

Lan

et al. 2023

Preprint

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Background The process of neuroinflammation is marked by the production of pro-inflammatory cytokines and leads to neuronal death. However, accumulating evidence suggests that classic inflammatory processes alone do not fully explain many aspects of neuroinflammation pathogenesis. Recent findings indicate that abnormal deposition of lipid droplet (LD) plays a crucial role in the pathogenesis of neuroinflammation. Microglia, which regulate neuronal activity have been implicated in LD aggregation during neuroinflammation. However, the regulatory mechanism of LDs in neurons remains poorly understood. Methods Neurons were stimulated with LPS-treated microglia supernatant. Immunostaining with BODIPY was used to determine the localization of LDs in different neuronal cell lines and culture systems. LAMP and LC3 were used as lysosomal markers for LD co-localization analysis. For in vivo studies, we used a sepsis-associated encephalopathy (SAE) mouse model to mimic neuroinflammation. Following microglia depletion using the small molecule CSF-1R inhibitor PLX3397, we examined lactate levels and LD changes in the mouse hippocampus. Results Our findings revealed activated microglia caused LD aggregation in neurons inducted by lactate. Furthermore, we observed co-localization of LDs with LAMP2 and LC3, suggesting involvement of the lysosomal pathway. These results were corroborated in an in vivo SAE model, where PLX3397 administration led to a reduction in LD accumulation and lactic acid levels. Conclusion Our study demonstrated that activated microglia induce LD accumulation in various neuronal cultures via the lactate-lysosome signaling pathway. A better understanding of the neuron lipid metabolism in the nervous system may ultimately contribute to the development of novel therapeutic strategies for neuroinflammation.

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Section: Discussioncontrasting

confidence: 99%

Regulation of neuronal lipid droplet aggregation by microglia through the lactate-lysosome signaling pathway

Lan

et al. 2023

Preprint

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“…On the other hand, the resting-balanced microglia phenotype (M0) with ramified appearance is the main type of microglia residing in the parenchyma of the healthy brain. Depending on the type of the exposed environment and the identified stimulus, M0 implies different phenotypes, whether M1/TH1 or M2/TH2 phenotype ( Guedes et al, 2018 ; Ji et al, 2019 ; Leng and Edison, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Assessing the role of primary healthy microglia and gap junction blocker in hindering Alzheimer’s disease neuroinflammatory type: Early approaches for therapeutic intervention

et al. 2023

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Alzheimer’s disease (AD) is a predominantly heterogeneous disease with a highly complex pathobiology. The presence of amyloid-beta (Aβ) depositions and the accumulation of hyperphosphorylated tau protein remain the characteristic hallmarks of AD. These hallmarks can be detected throughout the brain and other regions, including cerebrospinal fluid (CSF) and the spinal cord. Microglia cells, the brain-resident macrophage type of the brain, are implicated in maintaining healthy brain homeostasis. The localized administration of primary healthy microglia (PHM) is suggested to play a role in mitigating AD hallmark depositions and associated cognitive dysfunction. Carbenoxolone (CBX) is the most common gap junction blocker. It cannot effectively cross the blood–brain barrier (BBB) under systemic administration. Therefore, localized administration of CBX may be a recommended intervention against AD by acting as an antioxidant and anti-inflammatory agent. This study aims to determine whether the localized intracerebroventricular (ICV) administration of PHM and CBX may act as an effective therapeutic intervention for AD neuroinflammatory type. In addition, this study also aims to reveal whether detecting AD hallmarks in the spinal cord and CSF can be considered functional and effective during AD early diagnosis. Male albino rats were divided into four groups: control (group 1), lipopolysaccharide (LPS)-induced AD neuroinflammatory type (group 2), ICV injection of LPS + isolated PHM (group 3), and ICV injection of LPS + CBX (group 4). Morris water maze (MWM) was conducted to evaluate spatial working memory. The brain and spinal cord were isolated from each rat with the collection of CSF. Our findings demonstrate that the localized administration of PHM and CBX can act as promising therapeutic approaches against AD. Additionally, Aβ and tau toxic aggregates were detected in the spinal cord and the CSF of the induced AD model concomitant with the brain tissues. Overall, it is suggested that the ICV administration of PHM and CBX can restore normal brain functions and alleviate AD hallmark depositions. Detecting these depositions in the spinal cord and CSF may be considered in AD early diagnosis. As such, conducting clinical research is recommended to reveal the benefits of related therapeutic approaches compared with preclinical findings.

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“…Similar immune responses regarding most of those cytokines were also found in the CM of LPS induced BV-2 cells by the previous studies (Li et. al.,2016;Ji et. al., 2019).…”

Section: Discussionmentioning

confidence: 99%

Conditioned media of mouse macrophages promote neuronal differentiation of mouse hippocampal cells

Öztürk

Ayaz

2022

Preprint

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Understanding how the immune system associates with the pathophysiological hippocampal neurobiology in the neurodegenerative diseases is an emerging topic. Since the cellular population of hippocampal neurogenic niche is extraordinarily diverse, there is still a large gap in our understanding of the interactions between the immune cells and hippocampal neurons under even normal conditions, setting aside the disease conditions. To examine how the hippocampal neurons receive and respond to the cellular factors from the immune cells, we introduced the conditioned cell culture media (CM) of unstimulated, and lipopolysaccharide stimulated RAW 264.7 macrophages to HT22 hippocampal cells during and after they were exposed to neuronal differentiation environment to mimic the states during and after the initiation of the neurogenesis. Then, HT22 cell responses were further examined by assessing immunocytochemical expression of CR protein and mRNA levels of Ascl1, Bdnf, Nrf2 and Rac1 genes via semi quantitative image analysis and q-RT-PCR, respectively. Our results suggest that culturing the HT22 cells with the unstimulated CM of macrophages substantially increased calretinin protein expression, while the latter media containing quite high levels of inflammatory cytokines, measured by ELISA, resulted in decreased protein levels for Calretinin. Additionally, Ascl1 gene expression levels in HT22 cells had similar trends as calretinin protein levels in the presence of CM of stimulated versus unstimulated media. Whereas there was no substantial difference in the gene expression levels for the Bdnf, Nrf2 and Rac1 genes. Overall, our results imply that utilization of HT22 cells and macrophage interplay can be instructive to decipher the molecular mechanisms of cellular communication between the immune system cells and neurons. Our overarching aim is developing immunotherapy strategies by using non-CNS derived immune system cells to modulate the neurogenesis in disease conditions such as Multiple Sclerosis, Alzheimer’s and ALS to enable the recovery in the patients.

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Effects of Microglial Cytokines on Alzheimer’s Disease-Related Phenomena

Cited by 10 publications

References 58 publications

Regulation of neuronal lipid droplet aggregation by microglia through the lactate-lysosome signaling pathway

Regulation of neuronal lipid droplet aggregation by microglia through the lactate-lysosome signaling pathway

Assessing the role of primary healthy microglia and gap junction blocker in hindering Alzheimer’s disease neuroinflammatory type: Early approaches for therapeutic intervention

Conditioned media of mouse macrophages promote neuronal differentiation of mouse hippocampal cells

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