Inflammatory Response in the Hippocampus of PS1_M146L/APP_751SLMouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic

Abstract

Although the microglial activation is concomitant to the Alzheimer's disease, its precise role (neuroprotection vs neurodegeneration)has not yet been resolved. Here, we show the existence of an age-dependent phenotypic change of microglial activation in the hippocampus of PS1xAPP model, from an alternative activation state with A␤ phagocytic capabilities (at 6 months) to a classic cytotoxic phenotype (expressing TNF-␣ and related factors) at 18 months of age. This switch was coincident with high levels of soluble A␤ oligomers and a significant pyramidal neurodegeneration. In vitro assays, using astromicroglial cultures, demonstrated that oligomeric A␤42 and soluble extracts from 18-month-old PS1xAPP hippocampus produced a potent TNF-␣ induction whereas monomeric A␤42 and soluble extract from 6-or 18-month-old control and 6-month-old PS1xAPP hippocampi produced no stimulation. This stimulatory effect was avoided by immunodepletion using 6E10 or A11. In conclusion, our results show evidence of a switch in the activated microglia phenotype from alternative, at the beginning of A␤ pathology, to a classical at advanced stage of the disease in this model. This change was induced, at least in part, by the age-dependent accumulation of extracellular soluble A␤ oligomers. Finally, these cytotoxic activated microglial cells could participate in the neuronal lost observed in AD.

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…As expected (Jimenez et al, 2008; Serrano‐Pozo, Muzikansky, et al, 2013; Serrano‐Pozo, Betensky, Frosch, & Hyman, 2016; Trujillo‐Estrada et al, 2013), the hippocampus of both the transgenic APP/PS1 model and Alzheimer's patients (Braak V–VI) displays significant astrogliosis (measured by GFAP expression and by the area covered by the reactive astrocytes; see also Jimenez et al, 2008), which progresses in parallel to the extracellular amyloid pathology. The increase in astrocytic reactivity involves both morphological (enlarged cell body and processes) and molecular changes (Osborn et al, 2016).…”

“…These bigenic mice were obtained (see Blanchard et al, 2003) by crossing homozygous PS1 mice (expressing human mutant PS1[M146L] under HMGCoA reductase promoter) to hemizygous APP751SL mice (expressing human mutant APP751 carrying the Swedish [KM670/671NL] and London [V717I] mutations under the control of the Thy1 promoter). We have previously characterized this APP/PS1 transgenic model (Baglietto‐Vargas et al, 2010; Jimenez et al, 2008; Ramos et al, 2006; Sanchez‐Varo et al, 2012; Torres et al, 2012; Trujillo‐Estrada et al, 2014). Age‐matched non‐transgenic mice (WT) of the same genetic background (C57BL:6) were used as controls.…”

A Mouse Model of Amyloid β Oligomers: Their Contribution to Synaptic Alteration, Abnormal Tau Phosphorylation, Glial Activation, and Neuronal LossIn Vivo

“…A␤ oligomers have been demonstrated to cause these pathological changes in vitro when applied exogenously to cultured cells and brain slices (Hu et al, 1998;Lambert et al, 1998;Kayed et al, 2003;De Felice et al, 2008;Jimenez et al, 2008). However, it is still unclear whether A␤ oligomers have similar pathological effects in vivo.…”

“…Several studies have demonstrated that exogenously applied A␤ oligomers induce tau hyperphosphorylation (De Felice et al, 2008), activate astrocytes (Hu et al, 1998) and microglia (Jimenez et al, 2008), and cause neuronal death (Lambert et al, 1998; in vitro. However, in animal models, these findings have never been observed before amyloid plaque deposition (for review, see Duyckaerts et al, 2008).…”

Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression

“…M1 microglia are considered to be pro-inflammatory (releasing IL-1β, TNFα) and result in deleterious neuroinflammation while M2 (releasing IL-10, neurotrophins) are believed to promote neuroprotection and regeneration after injury (Olah et al, 2011, David and Kroner, 2011, Jimenez et al, 2008. Although minocycline is well-regarded as an inhibitor of microglial activation, recent evidence indicates that minocycline selectively inhibits microglial M1, but not M2, polarisation both in vitro and in an animal model of amyotrophic lateral sclerosis (Kobayashi et al, 2013).…”