**1. Introduction**

Neurodegenerative diseases represent a major public health issue in the world. Indeed, due to the progressive aging of the population and the lack of curative treatments, the number of people suffering from neurodegenerative diseases has increased considerably in recent years and is expected to continue to grow steadily in the years to come. These pathologies are chronic progressive diseases that affect the central nervous system, mainly the neurons that are often the target of therapies. The causes of these pathologies are to be found in genetics or risk factors such as the presence of chemical molecules in food, air, water, houses, and everyday objects. These different risk factors can contribute to oxidative stress, inflammation, and peroxisomal and mitochondrial dysfunctions, ultimately leading to neuronal death [1]. Most therapies target neurons and their function. However, there is an inflammatory component that must also be considered, and thus the involvement of microglia, in these pathologies [2]. Microglial cells are the major resident immune cells in the brain. Microglia activation is often classified into two opposite states: M1 and M2 [3]. The M1 state corresponds to a "classical activation" and is considered to be proinflammatory with a high capacity to present antigens, and high production of nitric oxide (NO) and reactive oxygen species (ROS) as well as pro-inflammatory cytokines. The M2 state includes both "alternative activation" and "acquired deactivation" and expresses the phenotypic markers arginase-1 (Arg1), CD206, interleukin (IL)-10, transforming growth

**Citation:** Charrière, K.; Ghzaiel, I.; Lizard, G.; Vejux, A. Involvement of Microglia in Neurodegenerative Diseases: Beneficial Effects of Docosahexahenoic Acid (DHA) Supplied by Food or Combined with Nanoparticles. *Int. J. Mol. Sci.* **2021**, *22*, 10639. https://doi.org/10.3390/ ijms221910639

Academic Editor: Fabrizio Michetti

Received: 2 September 2021 Accepted: 27 September 2021 Published: 30 September 2021

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factor β (TGF-β), and IL-1. This M2 state is considered to be an anti-inflammatory state [4] with the capacity to fine-tune inflammation, debris removal, promotion of angiogenesis, and tissue remodeling and repair. This separation into two opposite states does not reflect all the microglia phenotypes which will depend on the brain injury, its stage, and its location [2,5]. Nevertheless, microglial cells can be neuroprotective or neurotoxic depending on their activation status and the M1/M2 terminology remains useful to describe these two properties, while keeping in mind that it does not allow all reactive states of microglia to be described.

In physiological conditions, microglial cells work as sentinels. When they are activated by injurious stimuli, they can turn into several phenotypes, the two main ones being M1 and M2.

M1 produces pro-inflammatory cytokines that allow neuroprotection by removing pathological agents or recruiting additional cells. In this case, neuro-inflammation caused by microglia is neuroprotective. In contrast, a prolonged neuro-inflammation induces neurotoxicity and leads to neurodegeneration [6]. Briefly, M1 cells act as potent effectors that drive the inflammatory response, can have detrimental effects on neural cells, and participate in neuronal cell death if the switch to the M2 state does not occur in an appropriate time frame [7].

Therefore, modulating the activation state of microglia and their tendency toward the M2 state could be a promising therapeutic approach for central nervous system repair and regeneration.

Given the lack of effective treatment and the difficulty of developing a molecule capable of crossing the blood–brain barrier (BBB), the use of food-derived molecules has been raised as a possible therapeutic option to target the current inflammatory state or to improve the phagocytic activity of microglia. Among these molecules, docosahexaenoic acid (DHA; C22:6 omega-3), an omega-3 polyunsaturated fatty acid, has many advantages.

In this review, we will focus on the potential cytoprotective effects of DHA on oxidative stress, cell death affecting microglia, and on microglia-controlled inflammation. We will also present some human clinical trials that show the benefits of using DHA to improve the therapeutic management of patients with neurodegenerative diseases along with certain limits to the use of DHA in capsules or from food. Finally, we will present different approaches using nanoparticles that could allow for a better availability of DHA at the cerebral level.
