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Role of dietary fatty acids in microglial polarization in Alzheimer's disease.

ABSTRACT: Microglial polarization is an utmost important phenomenon in Alzheimer's disease that influences the brain environment. Polarization depends upon the types of responses that cells undergo, and it is characterized by receptors present on the cell surface and the secreted cytokines to the most. The expression of receptors on the surface is majorly influenced by internal and external factors such as dietary lipids. Types of fatty acids consumed through diet influence the brain environment and glial cell phenotype and types of receptors on microglia. Reports suggest that dietary habits influence microglial polarization and the switching of microglial phenotype is very important in neurodegenerative diseases. Omega-3 fatty acids have more influence on the brain, and they are found to regulate the inflammatory stage of microglia by fine-tuning the number of receptors expressed on microglia cells. In Alzheimer's disease, one of the pathological proteins involved is Tau protein, and microtubule-associated protein upon abnormal phosphorylation detaches from the microtubule and forms insoluble aggregates. Aggregated proteins have a tendency to propagate within the neurons and also become one of the causes of neuroinflammation. We hypothesize that tuning microglia towards anti-inflammatory phenotype would reduce the propagation of Tau in Alzheimer's disease.

SUBMITTER: Desale SE

PROVIDER: S-EPMC7093977 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Role of dietary fatty acids in microglial polarization in Alzheimer's disease.

Desale Smita Eknath SE Chinnathambi Subashchandrabose S

Journal of neuroinflammation 20200324 1

Microglial polarization is an utmost important phenomenon in Alzheimer's disease that influences the brain environment. Polarization depends upon the types of responses that cells undergo, and it is characterized by receptors present on the cell surface and the secreted cytokines to the most. The expression of receptors on the surface is majorly influenced by internal and external factors such as dietary lipids. Types of fatty acids consumed through diet influence the brain environment and glial ...[more]

PMID: 32209097

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Project description:PurposeThere is an ever-growing body of literature examining the relationship between dietary omega-3 polyunsaturated fatty acids (ω3 PUFAs) and cerebral structure and function throughout life. In light of this, the use of ω3 PUFAs, namely, long-chain (LC) ω3 PUFAs (i.e., eicosapentaenoic acid and docosahexaenoic acid), as a therapeutic strategy to mitigate cognitive impairment, and progression to Alzheimer's disease is an attractive prospect. This review aims to summarise evidence reported by observational studies and clinical trials that investigated the role of LC ω3 PUFAs against cognition impairment and future risk of Alzheimer's disease.MethodsStudies were identified in PubMed and Scopus using the search terms "omega-3 fatty acids", "Alzheimer's disease" and "cognition", along with common variants. Inclusion criteria included observational or randomised controlled trials (RCTs) with all participants aged ≥ 50 years that reported on the association between LC ω3 PUFAs and cognitive function or biological markers indicative of cognitive function linked to Alzheimer's disease.ResultsEvidence from 33 studies suggests that dietary and supplemental LC ω3 PUFAs have a protective effect against cognitive impairment. Synaptic plasticity, neuronal membrane fluidity, neuroinflammation, and changes in expression of genes linked to cognitive decline have been identified as potential targets of LC ω3 PUFAs. The protective effects LC ω3 PUFAs on cognitive function and reduced risk of Alzheimer's disease were supported by both observational studies and RCTs, with RCTs suggesting a more pronounced effect in individuals with early and mild cognitive impairment.ConclusionThe findings of this review suggest that individuals consuming higher amounts of LC ω3 PUFAs are less likely to develop cognitive impairment and that, as a preventative strategy against Alzheimer's disease, it is most effective when dietary LC ω3 PUFAs are consumed prior to or in the early stages of cognitive decline.

Project description:The study of microglia, the immune cells of the brain, has experienced a renaissance after the discovery of microglia polarization. In fact, the concept that activated microglia can shift into the M1 pro-inflammatory or M2 neuroprotective phenotypes, depending on brain microenvironment, has completely changed the understanding of microglia in brain aging and neurodegenerative diseases. Microglia polarization is particularly important in aging since an increased inflammatory status of body compartments, including the brain, has been reported in elderly people. In addition, inflammatory markers, mainly derived from activated microglia, are widely present in neurodegenerative diseases. Microglial inflammatory dysfunction, also linked to microglial senescence, has been extensively demonstrated and associated with cognitive impairment in neuropathological conditions related to aging. In fact, microglia polarization is known to influence cognitive function and has therefore become a main player in neurodegenerative diseases leading to dementia. As the life span of human beings increases, so does the prevalence of cognitive dysfunction. Thus, therapeutic strategies aimed to modify microglia polarization are currently being developed. Pharmacological approaches able to shift microglia from M1 pro-inflammatory to M2 neuroprotective phenotype are actually being studied, by acting on many different molecular targets, such as glycogen synthase kinase-3 (GSK3) ?, AMP-activated protein kinase (AMPK), histone deacetylases (HDACs), etc. Furthermore, nutritional approaches can also modify microglia polarization and, consequently, impact cognitive function. Several bioactive compounds normally present in foods, such as polyphenols, can have anti-inflammatory effects on microglia. Both pharmacological and nutritional approaches seem to be promising, but still need further development. Here we review recent data on these approaches and propose that their combination could have a synergistic effect to counteract cognitive aging impairment and Alzheimer's disease (AD) through immunomodulation of microglia polarization, i.e., by driving the shift of activated microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype.

Project description:BackgroundAging is the primary risk factor for the onset of Alzheimer's disease (AD). Inflamma-aging is a major feature in the process of aging, and the chronic neuroinflammation caused by inflamma-aging is closely related to AD. As the main participant of neuroinflammation, the polarization of microglia (MG) could influence the development of neuroinflammation.ObjectiveThis study aims to observe the impact of YHD on microglia (MG) polarization and neuroinflammation to delay the onset and progression of AD.MethodsIn vivo experiment, four-month senescence accelerated mouse prone 8 (SAMP8) were used as the model group, the SAMR1 mice of the same age were used as the control group. In YHD group, 6.24 g/kg YHD was intragastrically administrated continuously for 12 weeks, and Ibuprofen 0.026 g/kg in positive control group. Morris Water Maze test was used to evaluate the learning and memory ability, Nissl's staining and immunofluorescence double staining for neuron damage and MG M1/M2 polarization, Enzyme-Linked Immunosorbent Assay (ELISA) for neuroinflammation biomarkers in hippocampus, Western blot for key protein expression of TREM2/NF-κB signaling pathway. In vitro experiments, 10 μM/l Aβ1-42 induced BV-2 cell model was used to re-verify the effect of YHD regulating MG polarization to reduce neuroinflammation. Also, TREM2 small interfering RNA (siRNA) was used to clarify the key target of YHD.ResultsYHD could improve the learning and memory ability of SAMP8 mice evaluated by the Morris Water Maze test. Like Ibuprofen, YHD could regulate the M1/M2 polarization of MG and the levels of neuroinflammatory markers TNF-α and IL-10 in hippocampus, and relieve neuroinflammation and neuron loss. In addition, YHD could also regulate the expression of PU.1, TREM2, p-NF-κB P65 in the TREM2/NF-κB signaling pathway. Further in vitro experiments, we found that YHD had a significant regulatory effect on Aβ1-42-induced BV-2 cell polarization, and it could significantly increase PU.1, TREM2, decrease p-NF-κB P65, p-IKKβ, TNF-α, IL-6, IL-1β. At the same time, using siRNA to inhibit TREM2, it proved that TREM2 was a key target for YHD to promote Aβ1-42-induced BV-2 cell M2 polarization to reduce neuroinflammation.ConclusionsYHD could regulate the TREM2/NF-κB signaling pathway through TREM2, thereby to adjust MG polarization and reduce AD-related neuroinflammation.

Project description:The consumption of diets high in saturated fatty acids and/or refined carbohydrates are associated with neuroinflammation, cognitive dysfunction, and neurodegenerative disease. In contrast, diets high in polyunsaturated fatty acids are associated with anti-inflammatory and neuroprotective effects. We have previously shown that high fat diet (HFD) consumption increases saturated fatty acids and decreases polyunsaturated fatty acids in the hippocampus. We have further shown that HFD elicits exaggerated neuroinflammation and reduced synaptic elements, and results in robust memory deficits in aged rats. Here, we examined the impact of palmitate, an abundant dietary saturated fat, on a variety of cellular responses in BV2 microglia and HippoE-14 neurons, and the extent to which the omega-3 fatty acid, docosahexaenoic acid (DHA), would buffer against these responses. Our data demonstrate that DHA pretreatment prevents or partially attenuates palmitate-induced alterations in proinflammatory, endoplasmic reticulum stress, and mitochondrial damage-associated gene expression in both cell types. Furthermore, we show that synaptoneurosomes isolated from aged, HFD-fed mice are engulfed by BV2 microglia at a faster rate than synaptoneurosomes isolated from aged, chow-fed mice, suggesting HFD alters signaling at synapses to hasten their engulfment by microglia. Consistent with this notion, we found modest increases in complement proteins and a decrease in CD47 protein expression on synaptoneurosomes isolated from the hippocampus of aged, HFD-fed mice. Interestingly, palmitate reduced BV2 microglial phagocytosis, but only of synaptoneurosomes isolated from chow-fed mice, an effect that was prevented by DHA pretreatment. Lastly, we measured the impact of palmitate and DHA on mitochondrial function in both microglial and neuronal cell models using the Seahorse XFe96 Analyzer. These data indicate that DHA pretreatment does not mitigate palmitate-induced reductions in mitochondrial respiration in BV2 microglia and HippoE-14 neurons, suggesting DHA may be acting downstream of mitochondrial function to exert its protective effects. Together, this study provides evidence that DHA can ameliorate the negative impact of palmitate on a variety of cellular functions in microglia- and neuron-like cells.

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Role of dietary fatty acids in microglial polarization in Alzheimer's disease.

Publications

Role of dietary fatty acids in microglial polarization in Alzheimer's disease.

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