Phenomic Microglia Diversity as a Druggable Target in the Hippocampus in Neurodegenerative Diseases

Abstract

Phenomics, the complexity of microglia phenotypes and their related functions compels the continuous study of microglia in disease animal models to find druggable targets for neurodegenerative disorders. Activation of microglia was long considered detrimental for neuron survival, but more recently it has become apparent that the real scenario of microglia morphofunctional diversity is far more complex. In this review, we discuss the recent literature on the alterations in microglia phenomics in the hippocampus of animal models of normal brain aging, acute neuroinflammation, ischemia, and neurodegenerative disorders, such as AD. Microglia undergo phenomic changes consisting of transcriptional, functional, and morphological changes that transform them into cells with different properties and functions. The classical subdivision of microglia into M1 and M2, two different, all-or-nothing states is too simplistic, and does not correspond to the variety of phenotypes recently discovered in the brain. We will discuss the phenomic modifications of microglia focusing not only on the differences in microglia reactivity in the diverse models of neurodegenerative disorders, but also among different areas of the brain. For instance, in contiguous and highly interconnected regions of the rat hippocampus, microglia show a differential, finely regulated, and region-specific reactivity, demonstrating that microglia responses are not uniform, but vary significantly from area to area in response to insults. It is of great interest to verify whether the differences in microglia reactivity may explain the differential susceptibility of different brain areas to insults, and particularly the higher sensitivity of CA1 pyramidal neurons to inflammatory stimuli. Understanding the spatiotemporal heterogeneity of microglia phenomics in health and disease is of paramount importance to find new druggable targets for the development of novel microglia-targeted therapies in different CNS disorders. This will allow interventions in three different ways: (i) by suppressing the pro-inflammatory properties of microglia to limit the deleterious effect of their activation; (ii) by modulating microglia phenotypic change to favor anti-inflammatory properties; (iii) by influencing microglia priming early in the disease process.

Keywords: Alzheimer’s disease; LPS inflammation; TRPV2 channels; cannabidiol; inflammaging; ischemia; microbiota; reactive microglia; α7nACh receptor.

Figure 1

Diversity of microglia morphologies in the hippocampus. (A) Ramified, homeostatic microglia. IBA1: green (modified from [47]). Bar: 5 µm. (B) Jellyfish microglia in the ischemic CA1. IBA1: green, major histocompatibility complex type II (MHC II): red; merge: yellow–orange (modified from [48]). Bar: 2.5 µm. (C) Ball-and-chain-like structures at the end of microglia branches that can phagocytose small amounts of material. IBA1: green (modified from [49]). Bar: 5 µm. (D) Train of rod microglia in response to ischemia. IBA1: green; nuclei: blue (modified from [48]). Bar: 10 µm. (E) Phagoptotic microglia. IBA1: green; NeuN: red (modified from [50]). Bar: 5 µm. (F) Trogocytotic microglia. IBA1: green; NeuN: red (modified from [50]). Bar: 5 µm. (G) Amoeboid microglia with rounded morphology and phagocytosing pyknotic neurons after ischemia. IBA1: green; NeuN: red (modified from [48]). Bar: 10 µm. (H) Hyper-ramified microglia in CA1 of TGCRND8 mice. CD68: red (modified from [49]). Bar: 5 µm.

Figure 2

Representation of the different stages of microglia activation, in CA1 of organotypic hippocampal slices 24 h (A,B) and 36 h (C–C2) after OGD. Anti IBA1 antibody (green), anti MHC II antibody (blue), anti NeuN antibody (red). Colocalization of IBA1 (green) and MHC II (blue) is evidenced by the cyan colour (A,B). Scale bars: 25 µm (A); 10 µm (B,C1,C2); 50 µm (C) (modified from [48]).

Figure 3

Intense upregulation of α7AChNR in reactive plaque-associated microglia in CA1 and CA3 of TgCRND8 mice. Comparison with WT mice. Anti IBA1 antibody (blue), anti α7AChNR antibody (green), anti GFAP antibody (red). Empty arrows indicate Aβ plaques. (A) A microglia cell with faint α7AChNR immunofluorescence in CA1 hippocampus of WT mouse. (B) Ramified plaque-associated microglia with intense α7AChNR immunofluorescence in CA3 of a TgCRND8 mouse. (C) Amoeboid plaque-associated microglia with very intense α7AChNR immunofluorescence in CA1 of a TgCRND8 mouse. Astrocytes are also visible in red. Scale bar: 20 µm (from [202]).