Microglia in Alzheimer's Disease: Activated, Dysfunctional or Degenerative

Abstract

Microglial activation has been considered a crucial player in the pathological process of multiple human neurodegenerative diseases. In some of these pathologies, such as Amyotrophic Lateral Sclerosis or Multiple Sclerosis, the immune system and microglial cells (as part of the cerebral immunity) play a central role. In other degenerative processes, such as Alzheimer's disease (AD), the role of microglia is far to be elucidated. In this "mini-review" article, we briefly highlight our recent data comparing the microglial response between amyloidogenic transgenic models, such as APP/PS1 and AD patients. Since the AD pathology could display regional heterogeneity, we focus our work at the hippocampal formation. In APP based models a prominent microglial response is triggered around amyloid-beta (Aβ) plaques. These strongly activated microglial cells could drive the AD pathology and, in consequence, could be implicated in the neurodegenerative process observed in models. On the contrary, the microglial response in human samples is, at least, partial or attenuated. This patent difference could simply reflect the lower and probably slower Aβ production observed in human hippocampal samples, in comparison with models, or could reflect the consequence of a chronic long-standing microglial activation. Beside this differential response, we also observed microglial degeneration in Braak V-VI individuals that, indeed, could compromise their normal role of surveying the brain environment and respond to the damage. This microglial degeneration, particularly relevant at the dentate gyrus, might be mediated by the accumulation of toxic soluble phospho-tau species. The consequences of this probably deficient immunological protection, observed in AD patients, are unknown.

Keywords: APP models; Abeta plaques; Alzheimer disease; inflamation; microglia.

Figure 1

Microglial activation in APP/PS1 and microglial pathology in Alzheimer’s disease (AD) hippocampus. (A) Differential expression of selected microglial genes from hippocampus of 9- to 12-month-old APP/PS1 mice (age-matched wild-type (WT) as controls; n = 10 per genotype) and post-mortem human Braak V–VI samples (n = 28; age-matched non-demented BraaK II individuals as controls, n = 21) determined by qPCR analysis. Data were graphically plotted as Z-score and represented the deviation in the expression of a gene over the mean expression of this particular gene in the control populations (WT or Braak II). Each bar represented an individual murine or human sample. High expression is marked by the red color spectrum, low expression by blue colors. (B) Immunohistochemical detection of microglial cells around amyloid plaques in 12-month old APP/PS1 mice (b1,b2), human AD brains staged as Braak IV (b3,b4) or Braak V–VI (b5,b6). Amyloid plaques are surrounded by abundant activated Iba1-positive (b1) and CD45-positive (b2) microglia in the transgenic mice. Human plaques also displayed Iba1-positive and CD45-positive associated microglia at Braak IV stage, however the presence of amyloid deposits devoid of Iba1-positive microglia was often present in the hippocampus of Braak V–VI cases. Asterisks indicate amyloid plaques. BV, blood vessel. Scale bars (b1–b4) 20 μm; (b) 200 μm; (b6) 50 μm. (C,D) The Iba1-load quantitative analysis revealed a regional pattern with DG>CA3>CA1>parahippocampal gyrus (PHG) in Braak II (C,c1–4,D, green circles). In Braak V–VI individuals a significant (p < 0.05, Mann Whitney test) reduction of the microglial load was evidenced in the DG and CA3 regions (D, orange squares). (E) Compared to Braak II microglial cells (e1 shows a non-activated healthy Iba1-positive microglial cell), Braak V–VI cases exhibit microglial cells with degenerative morphological features including deramification (e2), fragmentation (e3), beadings and spheroidal swellings (e4,e5) and dystrophies (e6) of the processes. h, hilar region; g, granular layer; m, molecular layer; so, stratum oriens; sp, stratum pyramidale; sl, stratum lucidum; sr, stratum radiatum. Scale bars, (c1–8) 100 μm; (e1–6) 20 μm. (F) Differential accumulation of soluble Aβ and phospho-tau forms in the hippocampus of human Braak II and Braak V–VI brains. Quantitative data from dot blots or western blots of soluble S1 fractions (extracellular/cytosolic) isolated from Braak II (n = 8) or Braak V–VI (n = 8) individuals. The relative abundance of A11 or OC positive Abeta oligomers, AT8 or AT100 phospho-tau proteins was determined by densitometry analysis. Significance was determined by Mann Whitney test. (G) Soluble phospho-tau toxicity on BV2 microglial cells. Microglia were incubated with S1 fractions isolated from Braak II, V–VI samples or 18-month-old APP/PS1 or 12-month-old Thy1-tau22 models. The toxicity was analyzed by flow cytometry and the percent of viable cells was showed. The Aβ or phospho-tau was immunodepleted from the Braak V–VI S1 fractions using 6E10 plus 82E1 or AT8 plus AT100 antibodies, respectively. The data are shown as the mean ± SD of six different experiments. Significance (indicated in the figure) was determined by ANOVA and Tukey post hoc test. Data were taken from Jimenez et al. (2008, 2014); Moreno-Gonzalez et al. (2009); Sanchez-Mejias et al. (2016); Baglietto-Vargas et al. (2017) and Gutierrez and Vitorica (2018).

Figure 2

Dissimilar progressions of hippocampal microglial response in APP/PS1 mice and human brains. (A) Illustrate the age-dependent microglial activation in the amyloidogenic model from 4 (left) to 12 (right) months of age. Activated microglia characterized by morphological changes (hypertrophy of cell body and shortened processes) selectively cluster around amyloid plaques at early ages. Increased amyloid load with age is associated with expansion of the microglial activation. The age-dependent accumulation of soluble Aβ oligomers induces the activation of the interplaque microglia in aged transgenic mice. (B) Illustrate the microglial response during the course of AD pathology in the hippocampus of human brains. Amyloid pathology is a late event in the hippocampus while tau pathology shows a very early onset. In Braak III–IV hippocampus, some amyloid plaques are present and they are surrounded by activated microglia, however in late stage AD (Braak V–VI) microglial-bare plaques are usually found. The high content of phospho-tau forms (intra- and/or extracellular) induces the degeneration of microglial cells in human Braak V–VI hippocampus.