Nutritional and Pharmacological Strategies to Regulate Microglial Polarization in Cognitive Aging and Alzheimer’s Disease

Abstract

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) β, 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.

How to reprogram microglia toward beneficial functions

“…Other groups of bioactive compounds, normally present in foods, especially in the Mediterranean diet, such as phenolic compounds, phytosterols and carotenoids (e.g., lycopene, fucoxanthin, and lutein) exhibit anti‐inflammatory properties on microglia (Pena‐Altamira et al, ; Jeong et al, ; Sachdeva & Chopra, ; D. Zhao, Kwon, Chun, Gu, & Yang, ), but the mechanisms underlined their effects still remain to be defined.…”

Phenolic Compounds Characteristic of the Mediterranean Diet in Mitigating Microglia-Mediated Neuroinflammation

“…At the same time their poor diagnosis and lack of effective treatment worsens the problem ( Figueira et al, 2017 ; Pennisi et al, 2017 ). Since their prevalence remains growing, they currently represent a challenge for society and healthcare systems ( Deak et al, 2015 ; Peña-Altamira et al, 2017 ). Although age is the main risk factor for dementia, there are other recognized risk factors, quite a number of them related with diet such as mid-life hypertension, obesity or unbalanced diets ( WHO, 2018 ).…”

“…Hence, neurodegenerative disorders are recognized to be complex, progressive and multifactorial. At the same time genetic factors are associated since familial and sporadic forms are described with lifestyle and environmental factors involved ( Nicolia et al, 2014 ; Peña-Altamira et al, 2017 ).…”

“…The mechanisms by which polyphenols are able to prevent and counteract neurodegenerative diseases include interfering with amyloid aggregation, reducing oxidative stress and regulating signaling pathways and cytokines expression, with a marked effect on reducing inflammation ( Ramassamy, 2006 ; Essa et al, 2012 ; Martínez-Huélamo et al, 2017 ; Sarubbo et al, 2017 ). In fact, inflammatory markers, many of them derived from activated microglia, are widely present in neurodegenerative diseases and polyphenols have been proposed as active agents having anti-inflammatory effects on microglia ( Sundaram and Gowtham, 2012 ; Peña-Altamira et al, 2017 ; Cayero-Otero et al, 2018 ). Despite the broad evidence supported by both in vitro and in vivo studies, it is worth highlighting that we should be cautious when extrapolating the findings based on cell culture or animal research to the human disease.…”

Role of Nutraceuticals in Modulation of Gut-Brain Axis in Elderly Persons

“…Moreover in diabetic rats, eugenol administration results in reduction of oxidative markers in brain with restoration of activities of mitochondrial complexes I, II and III [55,56]. Other polyphenols (anthocyanin extract, pomegranate or resveratrol), exerted their anti-inflammatory effects by reducing TNF-a brain level and microgliosis or sirtuin activation in correlation with improving brain plasticity in non-transgenic AD animal models [57,58]. Resveratrol positive effects were also related to the activation of AMP-activated kinase (AMPK) and the antioxidant transcription factorNrf2 (nuclear factor (erythroid derived 2)-like 2) [59].…”