Abstract
Amyloid-beta oligomers (AβO) have been proposed as the most potent neurotoxic and inflammation inducers in Alzheimer’s disease (AD). AβO contribute to AD pathogenesis by impairing the production of several cytokines and inflammation-related signaling pathways, such as the Janus kinases/signal transducer of transcription factor-3 (JAK/STAT3) pathway. STAT3 modulates glial activation, indirectly regulates Aβ deposition, and induces cognitive decline in AD transgenic models. However, in vivo studies using an AβO microinjection rat model have not yet explored STAT3 role. The main purpose of this study was to elucidate if a single microinjection of AβO could promote an increased expression of STAT3 in glial cells favoring neuroinflammation and neurodegeneration. We designed a model of intrahippocampal microinjection and assessed glial activation, cytokines production, STAT3 expression, and neurodegeneration in time. Our results showed robust expression of STAT3 in glial cells (mainly in astrocytes) and neurons, correlating with neuronal death in response to AβO administration. A STAT3 inhibition assay conducted in rat primary hippocampal cultures, suggested that the induction of the transcription factor by AβO in astrocytes leads them to an activation state that may favor neuronal death. Notwithstanding, pharmacological inhibition of the JAK2/STAT3 pathway should be focused on astrocytes because it is also essential in neurons survival. Overall, these findings strongly suggest the participation of STAT3 in the development of neurodegeneration.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative condition characterized by the presence of intracellular neurofibrillary tangles and extracellular neuritic plaques (NP), induced by beta-amyloid (Aβ) peptide accumulation
Neuronal degeneration was evaluated with the Fluoro-Jade B (FJB) staining in rats sacrificed at 18 h, 72 h, and 7, 15, and 30 days after AβO microinjection
FJB positive cells were evident in the dentate gyrus (DG) region of AβO microinjected rats sacrificed at 72 h and 7 days post-injection
Summary
Alzheimer’s disease (AD) is a neurodegenerative condition characterized by the presence of intracellular neurofibrillary tangles and extracellular neuritic plaques (NP), induced by beta-amyloid (Aβ) peptide accumulation. The Aβ aggregation hypothesis has been proposed as the central mechanism underlying the development of the disease, yet it is still controversial [1,2,3]. Several reports have indicated that high molecular weight oligomers alter the integrity of the membrane by favoring the generation of ROS and lipid peroxidation. This leads to a decrease in membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP [12]. AβO cause synaptic plasticity dysfunction, cognitive impairment, and cell death through the extracellular interaction with the N-methyl-d-aspartate receptor (NMDAR) [14,15,16]
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