The relationships between neuroglial alterations and neuronal changes in Alzheimer's disease, and the related controversies I: Gliopathogenesis and glioprotection

Abstract

Since Alois Alzheimer described the pathology of Alzheimer's disease in 1907, an increasing number of studies have attempted to discover its causes and possible ways to treat it. For decades, research has focused on neuronal degeneration and the disruption to the neural circuits that occurs during disease progression, undervaluing in some extent the alterations to glial cells even though these alterations were described in the very first studies of this disease. In recent years, it has been recognized that different families of neuroglia are not merely support cells for neurons but rather key and active elements in the physiology and pathology of the nervous system. Alterations to different types of neuroglia (especially astroglia and microglia but also mature oligodendroglia and oligodendroglial progenitors) have been identified in the initial neuropathological changes that lead to dementia, suggesting that they may represent therapeutic targets to prevent neurodegeneration. In this review, based on our own studies and on the relevant scientific literature, we argue that a careful and in-depth study of glial cells will be fundamental to understanding the origin and progression of Alzheimer's disease. In addition, we analyze the main issues regarding the neuroprotective and neurotoxic role of neuroglial changes, reactions and/or involutions in both humans with Alzheimer's disease and in experimental models of this condition.

Keywords: Alzheimer´s disease; astroglia; astrogliosis; gliopathogenesis; glioprotection; microglia; microgliosis; oligodendroglia.

Figure 1.

Brodmannn's area 46 of a brain from an AD case, Braak and Braak V. Layer IV-V. Zone of high density of glial cells scattered in the cortical parenchyma and not related to amyloid plaques. Congo red stain / confocal observation with green filter. A large number of neuroglial nuclei (from astrocytes, oligodendrocytes, and microglial cells) is observed. The technique does not allow to differentiate the different types or subtypes of neuroglial cells, but it demonstrates the high density of neuroglial cells that are present in this region of the CNS altered by AD pathology. Bar = 200 microns

Figure 2.

Brodmannn's area 46 of a brain from an AD case, Braak and Braak V. Layer II / III. Area of low incidence of glial cells. Bielschowsky silver impregnation. The intensely stained nuclei correspond mostly to microglial cells and are largely associated with amyloid plaques, both with and without “core”. Bar = 150 microns

Figure 3.

Brodmannn's area 46 of a brain from an AD case, Braak and Braak V. Layer I / II. Area of low density of neuroglial cells, especially astrocytes. Section immunostained with amyloid antibody 6E10 plus hematoxylin contrast. Amyloid plaques and small deposits of intraparenchymal amyloid are observed. Many of the astroglial cells (arrows) (confirmed in parallel sections immunostained with GFAP antibody) show amyloid reaction. Bar = 150 microns

Figure 4.

A and B. Brodmann’s area 46 of a brain from an AD case, Braak and Braak IV. GFAP immunostaining plus hematoxylin staining contrast. Fig. 4A. Layer V. Zone of high density of hypertrophic GFAP hyper-reactive astroglial cells scattered in the cortical parenchyma, mostly related to dystrophic neurons but not to amyloid plaques. A large number of glial nuclei (oligodendrocytes and microglial cells, as well as GFAP immunonegative astroglial cells) is observed. Fig 4B. Small area of this zone where hypertrophic astrocytes are observed in the process of klasmatodendrosis, with a great fragmentation of their glial extensions. Bar, Fig 4A = 50 microns; Fig 4B = 40 microns.

Figure 5.

Astroglial cells (GFAP immunostaining) in a case of AD, Braak and Braak IV. CA1 region of the hippocampus. Highly complex amyloid plaques with a variable "crown" of hypertrophic and hyperreactive astrocyte cells. Astrocytic extensions barely penetrate the plaques. (Hematoxylin contrast). Bar = 100 microns.

Figure 6.

Brodmann's area 46, layer I / III. Different types of clusters of astroglial cells randomly dispersed and with little relation to amyloid plaques (revealed in a parallel section) (without H / E contrast). Bar = 200 microns

Figure 7

. Brodmann's area 46, layer V. High incidence of hypertrophic and hyperreactive astrocytes surrounding a large amyloid plaque and relating to vessels and neurons of normal appearance in this layer. Bar = 100microns.

Figure 8.

Small foci of hypertrophic astrocyte clusters - hyperreactive GFAPs, unrelated to amyloid deposits and / or dystrophic neurons, in one case of AD, Braak and Braak, III, Brodmann's area 46. GFAP immunostaining plus hematoxylin contrast. No amyloid plaques were demonstrated in parallel sections. Bar = 40 microns.

Figure 9.

Small foci of hypertrophic astrocyte clusters - hyperreactive GFAPs, unrelated to amyloid deposits and / or dystrophic neurons, in one case of AD, Braak and Braak, III, Brodmann's area 7. GFAP immunostaining plus hematoxylin contrast. No amyloid plaques were demonstrated in parallel sections. Bar = 40 microns.

Figure 10.

Cerebellum (vermis, lobe VI) of a case of AD, Braak and Braak, III. GFAP immunostaining. Hyperreactive normal and hypertrophic / GFAP astroglial cells are observed, both stellate and elements of the Golgi epithelial glia, as well as numerous astroglial nuclei of hyperplasic GFAP immunonegative astroglia. Bar = 150 microns.

Figure 11.

Cerebellum (vermis, lobe VI) of a case of AD, Braak and Braak, III. Nitrotyrosine immunostaining (degenerative reaction marker). Staining is observed in most of the hyperplasic cells in the Purkinje cell layer. Bar = 150 microns.

Figure 12.

Microglia cells in a case of AD, Braak and Braak III, Brodmann's area 46, layer IV / V. IBA-1 immunostaining. High density of microglial cells with abundant extensions that are scattered throughout the parenchyma. Bar = 50 microns.

Figure 13.

Microglia cells in a case of AD, Braak and Braak III, Brodmann's area 46, layer IV / V. Lectin immunostaining. High density of microglial cells, both with rounded morphology and with extensions, scattered throughout the parenchyma. The forms with extensions invade the amyloid plates. Bar = 50 microns.

Figure 14.

A and B. Microglia cells in a case of AD, Braak and Braak III, Brodmann's area 46, layer IV / V. Silver impregnation, Bielchowsky block method. Amyloid plaques ((Bar = A, 65 microns and B, 50 microns of diameter) without core (A) and with core (B) showing microglial invasion.

Figure 15.

Electron microscopy image of an amyloid plaque of the frontoparietal cortex (layer V) in a transgenic model of AD (APP + PS1, to which two human genes have been inserted - Amiloid Precursor Protein and Pre-Seniline 1- that induce AD of family type). In the center of the image, an amyloid plaque is observed, with a dense amyloid “core” and less electrodense radial amyloid extensions. The boundaries of a hypertrophic astroglial cell are marked in red, and the extensions of a microglial cell associated to the amyloid plaque are marked in blue. In black, hypertrophic neurites filled with vesicular forms indicative of degeneration of dendrites and axons of affected neurons are delimited. The almost “normal” appearance neuropil shows small alterations compared to control mice (increase in diameter and alterations of subcellular structures in dendrites and axons; synaptic alterations; varicosities in neuroglia extensions). Bar = 25 microns

Figure 16.

Scheme where the complex relationships between the various morpho-functional forms (normal, reactive, dystrophic, “senescent” – these currently valued for their expression of specific macromolecules [240-242] of the main neuroglial types with the accompanied neurons (both normal and dystrophic) are considered. Neuroglia cells maintain close interrelationships (“crosstalk of glial cells”) [209, 243] offering a modulate response of the entire neuroglial group on neurons, both normal and dystrophic. Neuroactive neuroglia glial substances (cytokines, chemokines, prostaglandins, NO, free radicals, etc), can finally produce (directly or in-directly) neurotoxicity/neuronal involution or stimulate neuronal recovery. In the first case, the first action could tend to eliminate neurotoxic neurons to improve homeostasis, but in the case of AD can spread neurodegeneration in degenerating areas.