Hypoxia and alzheimer's disease: the processing of amyloid precursor protein and the role of prolyl-hydroxylase 3 in microglia

Resumen

Recent epidemiological evidence has revealed an association between the development of Alzheimer’s disease (AD) and hypoxia-associated conditions. In this sense, a number of in vitro and in vivo studies have attributed this comorbidity to elevated amyloid-β (Aβ) accumulation by different hypoxia-mediated mechanisms, including Aβ precursor protein (AβPP) up-regulation, decreased levels of Aβ-degrading enzymes, and an enhanced amyloidogenic AβPP processing. However, approaches of hypoxia/reoxygenation, not hypoxia fine-controlled conditions, or even asphyxiation strategies have been utilized in these studies. We used accurately controlled hypoxia expositions in chambers to induce pure acute or chronic sustained hypoxia in wild-type and App/Psen1 mice. In spite of the fact that our protocols elicited a remarkable hypoxic response, no substantial changes were observed after acute or chronic treatment in Aβ-related genes, AβPP processing by-products, or Aβ peptide levels, arguing against a hypoxia induced Aβ accumulation. As hypoxia has profound effects on immune system physiology and Genome Wide Association-Studies presented evidence for a prominent role of innate immunity in AD, we characterized microglia, the resident macrophages of the central nervous system, response to hypoxia. We found that Egln3, the gene encoding for prolyl 4-hydroxylase domain 3 (PHD3) protein, was the most induced gene in hypoxia, intriguingly resembling its expression in AD microglia. Given the comorbidity between hypoxia-related conditions and AD, and the strong induction of Egln3 in both scenarios, we depleted this gene to explore its potential role in the disease. PHD3 depleted AD mouse models presented increased CD45 microglial marker, coincident with a moderate rise in microglial Aβ uptake that corresponded to a reduction in Aβ peptide content and changes in amyloid deposits. Furthermore, PHD3 deficient AD mouse models showed a closer proximity of their microglia to amyloid plaques and less neuronal dystrophy, something consistent with the observed recovery of motor and short-term memory defects exhibited by AD mouse models. Microarray analysis from adult isolated microglia from PHD3 deficient AD mice revealed a remarkable repression of anti-microbial responses, with special emphasis on anti-viral responses, and potentiation of other transcriptional responses already present in AD microglia. This potentiation was accompanied by a decrease in the mRNA levels of Cd33, whose increased levels have been suggested as a risk factor for AD. Collectively, these data suggest that hypoxia does not affect Aβ-related genes or AβPP processing by-products but can induce the transcription of Egln3 in microglia, whose expression is associated with detrimental outcomes for AD. We also hypothesize that the regulation of sterile transcriptional modules, like anti-microbial modules in AD, can potentiate a beneficial microglial phenotype in terms of AD outcome while place PHD3 as a potential target for AD therapeutic.