BackgroundMicroglia are dependent upon colony-stimulating factor 1 receptor (CSF1R) signaling for their survival in the adult brain, with administration of the dual CSF1R/c-kit inhibitor PLX3397 leading to the near-complete elimination of all microglia brainwide. Here, we determined the dose-dependent effects of a specific CSF1R inhibitor (PLX5622) on microglia in both wild-type and the 3xTg-AD mouse model of Alzheimer’s disease.MethodsWild-type mice were treated with PLX5622 for up to 21 days, and the effects on microglial numbers were assessed. 3xTg-AD mice were treated with PLX5622 for 6 or 12 weeks and effects on microglial numbers and pathology subsequently assessed.ResultsHigh doses of CSF1R inhibitor eliminate most microglia from the brain, but a 75 % lower-dose results in sustained elimination of ~30 % of microglia in both wild-type and 3xTg-AD mice. No behavioral or cognitive deficits were found in mice either depleted of microglia or treated with lower CSF1R inhibitor concentrations. Aged 3xTg-AD mice treated for 6 or 12 weeks with lower levels of PLX5622 resulted in improved learning and memory. Aβ levels and plaque loads were not altered, but microglia in treated mice no longer associated with plaques, revealing a role for the CSF1R in the microglial reaction to plaques, as well as in mediating cognitive deficits.ConclusionsWe find that inhibition of CSF1R alone is sufficient to eliminate microglia and that sustained microglial elimination is concentration-dependent. Inhibition of the CSF1R at lower levels in 3xTg-AD mice prevents microglial association with plaques and improves cognition.

No abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body’s key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

Kinins are a family of peptides implicated in several pathophysiological events. Most of their effects are likely mediated by the activation of two G-protein-coupled receptors: B 1 and B 2 . Whereas B 2 receptors are constitutive entities, B 1 receptors behave as key inducible molecules that may be upregulated under some special circumstances. In this context, several recent reports have investigated the importance of B 1 receptor activation in certain disease models. Furthermore, research on B 1 receptors in the last years has been mainly focused in determining the mechanisms and pathways involved in the process of induction. This was essentially favoured by the advances obtained in molecular biology studies, as well as in the design of selective and stable peptide and nonpeptide kinin B 1 receptor antagonists. Likewise, development of kinin B 1 receptor knockout mice greatly helped to extend the evidence about the relevance of B 1 receptors during pathological states. In the present review, we attempted to remark the main advances achieved in the last 5 years about the participation of kinin B 1 receptors in painful and inflammatory disorders. We have also aimed to point out some groups of chronic diseases, such as diabetes, arthritis, cancer or neuropathic pain, in which the strategic development of nonpeptidic oral-available and selective B 1 receptor antagonists could have a potential relevant therapeutic interest.