Amyloid Peptide Induced Neuroinflammation Increases the P2X7 Receptor Expression in Microglial Cells, Impacting on Its Functionality

Abstract

Alzheimer disease is a neurodegenerative disease characterized by the presence of senile plaques composed of amyloid-β (Aβ) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have revealed that extracellular ATP, through its selective receptor P2X7 (P2X7R), is essential to neuroinflammation and neurotoxicity induced by Aβ. P2X7R is upregulated on microglial cells around the senile plaques. This upregulation progressively rises with age and is parallel with an accumulation of senile plaques and also correlates with the synaptic toxicity detected both in animal models reproducing AD and human patients of AD. Furthermore, the late onset of the first AD-associated symptoms suggests that aging associated-changes may be relevant to the disease progression. Thus, microglia motility and its capacity to respond to exogenous ATP stimulus decrease with aging. To evaluate whether the P2X7R age related-changes on microglia cells may be relevant to the AD progression, we generated a new transgenic mouse model crossing an Aβ peptide mouse model, J20 mice and the P2X7R reporter mice P2X7R EGFP. Our results indicate that neuroinflammation induced by Aβ peptide causes changes in the P2X7R distribution pattern, increasing it s expression in microglial cells at advanced and late stages, when microgliosis occurs, but not in the early stages, in the absence of microgliosis. In addition, we found that P2X7R activation promotes microglial cells migration to senile plaques but decreases their phagocytic capacity. Moreover, we found a significant reduction of P2X7R transcription on neuronal cells at the early and advanced stages, but not at the late stages. Since previous studies have reported that either pharmacological inhibition or selective downregulation of P2X7R significantly improve behavioral alterations and reduce the incidence and size of senile plaques in the early and advanced stages of AD, the results presented here provide new evidence, indicating that this therapeutic approach could be also efficient in the late stages of the disease.

Exploring the Role of P2X Receptors in Alzheimer’s Disease

“…The data suggested that this effect was caused by the neuroinflammation produced in these mice, and that ATP could act as a chemotaxis signal for microglial cells through the activation of P2X7, which lead the microglial cells to the senile plaques. Interestingly, they also found that P2X7R activation reduced the phagocytic capacity of these cells (Martinez-Frailes et al, 2019). Recently, it has been described that in the APPPS1 transgenic mice P2X7R deficiency reduces the cognitive impairment and the number of Aβ plaques and soluble species, although they did not observed significantly differences in the Aβ phagocytosis and the activation state of microglia (Martin et al, 2019).…”

“…This same study observed that BBG prevented the reduction in dendritic filopodia and density of spines induced by Aβ in hippocampal primary cultures (Fan et al, 2014). Recently, a more in-depth study of P2X7 expression was performed in a transgenic mouse model produced by breeding the J20AD mouse model (which overexpresses APP with the Swedish and Indiana mutations) and P2X7R EGFP reporter mice, which expresses this fluorescent protein under the control of the P2X7 promoter (Martinez-Frailes et al, 2019). In this model, they observed that in advanced stages of the disease, once microgliosis could be detected, the expression of P2X7 increased in microglial cells, and the number of microglial cells that expressed P2X7 also increased and were mainly localized on senile plaques.…”

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

“…Levels of cytotoxic and helper T-cells are upregulated in brain parenchyma of AD patients (Oberstein et al, 2018). Helper T cells and pro-inflammatory cytokines target neurofibrillary tangles and plaques composed of Aβ and Tau and activate microglia at these sites, further exacerbating neuroinflammation (Gold et al, 2014;Martinez-Frailes et al, 2019). One class of cytokines, called chemokines, stimulates leukocyte migration from blood to tissues.…”

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

“…In an elegant approach, Tg(P2X7-EGFP) mice were crossed with the J20 hAPP mice which express a mutant form of the human amyloid protein precursor [ 164 ]. Thereby the distribution of the P2X7R message could be observed in a well-established Alzheimer mouse model.…”