Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease

Abstract

Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer’s disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies.Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer’s disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits.In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer’s disease.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0606-1) contains supplementary material, which is available to authorized users.

Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model

“…Of note, in a recent study employing hippocampal virus-mediated overexpression of the Stat3 oppressor Socs3, altered genetic profiles and amyloid load were detected, but only marginal effects on cognition and phagocytosis (Ceyzeriat et al, 2018) A-D SH-4-54 significantly decreased plaque growth, as assessed by IC16 immunohistochemistry, while plaque load remained unchanged. Hence, our data indicate that both microglia and astrocytes can reciprocally initiate and execute pathways relevant for neuronal demise or recovery.…”

Questions and (some) answers on reactive astrocytes

“…Owing to refined methods to isolate astrocytes and investigate their transcriptome at the genome‐wide level, recent studies revealed that astrocyte reaction involves massive transcriptional changes that go well beyond Gfap induction. Hundreds of genes are either up‐regulated or down‐regulated in astrocytes in AD models and patients (Ceyzériat et al, ; Orre et al, ; Sekar et al, ), in a mouse model of hyperammonia (Lichter‐Konecki, Mangin, Gordish‐Dressman, Hoffman, & Gallo, ), or multiple sclerosis (MS) (Itoh et al, ), following spinal cord injury [SCI, (Anderson et al, )], cortical stab wound injury [SWI, (Sirko et al, )], middle cerebral artery occlusion (MCAO), or lipopolysaccharide (LPS) injection (Zamanian et al, ). Several genes induced in reactive astrocytes both in the LPS and MCAO models were identified.…”

“…In a complex in vivo multicellular environment with multiple stimuli, reactive astrocyte diversity may even be stronger. Both A1 and A2 genes are induced concomitantly in different models, such as mouse models of AD (Ceyzériat et al, ), Tauopathy (Litvinchuk et al, ), or ischemia (Liddelow et al, ).…”

“…Indeed, even reactive astrocytes activated by the same pathway can have different effects on specific disease outcomes. STAT3 signaling in reactive astrocytes has detrimental effects in mouse models of AD (Ceyzériat et al, ; Reichenbach et al, ), or hypoxia (Hristova et al, ), no significant effect in the context of acute mitochondria toxicity (O'Callaghan et al, ) but has beneficial effects in neonatal white matter injury (Nobuta et al, ), after SCI, by promoting glial scar formation (Anderson et al, ; Herrmann et al, ; Okada et al, ), and in HD models, by reducing mutant Huntingtin aggregation (Ben Haim, Ceyzeriat, et al, ). Intriguingly, a recent study by Tyzack et al () suggested that the upstream activator (IL6 or EphB1‐ephrine‐B1 signaling) controls the final molecular profile induced by STAT3 in reactive astrocytes (Table ).…”

“…Reactive astrocytes express nestin and other makers of neural stem cells (Gotz et al, ). Likewise, transcriptomic studies reveal that reactive astrocytes overexpress many genes characteristic of microglia (e.g., Cst7 , Trem2 , and Cts ) (Ceyzériat et al, ; Orre, Kamphuis, Osborn, Jansen, et al, ). Indeed, cells co‐expressing astrocyte and microglia markers are observed in the spinal cord of an ALS rat model (Trias et al, ), the deafferented mouse hippocampus or the brain of AD, Lewy body dementia, or stroke patients (Wilhelmsson et al, ).…”