CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer's disease model.

Chemokines are important modulators of neuroinflammation and neurodegeneration. In the brains of Alzheimer's disease (AD) patients and in AD animal models, the chemokine CXCL10 is found in high concentrations, suggesting a pathogenic role for this chemokine and its receptor, CXCR3. Recent studies aimed at addressing the role of CXCR3 in neurological diseases indicate potent, but diverse, functions for CXCR3. Here, we examined the impact of CXCR3 in the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. We found that, compared with control APP/PSI animals, plaque burden and Aß levels were strongly reduced in CXCR3-deficient APP/PS1 mice. Analysis of microglial phagocytosis in vitro and in vivo demonstrated that CXCR3 deficiency increased the microglial uptake of Aß. Application of a CXCR3 antagonist increased microglial Aß phagocytosis, which was associated with reduced TNF-α secretion. Moreover, in CXCR3-deficient APP/PS1 mice, microglia exhibited morphological activation and reduced plaque association, and brain tissue from APP/PS1 animals lacking CXCR3 had reduced concentrations of proinflammatory cytokines compared with controls. Further, loss of CXCR3 attenuated the behavioral deficits observed in APP/PS1 mice. Together, our data indicate that CXCR3 signaling mediates development of AD-like pathology in APP/PS1 mice and suggest that CXCR3 has potential as a therapeutic target for AD.

Impact and Therapeutic Potential of PPARs in Alzheimer's Disease.

Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metabolism, but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and, Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases, lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the deposition of the ß-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models. Stimulation of PPARγ by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising results using PPARγ agonists, therefore PPARγ represents an attractive therapeutic target for the treatment of AD.

Differential distribution of PDE4B splice variant mRNAs in rat brain and the effects of systemic administration of LPS in their expression.

Phosphodiesterases (PDE) control intracellular cyclic adenosine monophosphate (cAMP) levels, which appear to play an important role in the regulation of inflammation. PDE4B is especially important in this process. Using in situ hybridization histochemistry we first mapped the expression sites of the four PDE4B splicing forms in rat brain. Using the systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) as an inflammation model in rats, we found an increase in PDEB2 mRNA expression in choroid plexus. The differential expression of PDE4B spliced forms and the differential regulation of PDE4B2 in an inflammatory model further supports an involvement of this splicing variant in the inflammatory response.

Selective induction of cAMP phosphodiesterase PDE4B2 expression in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) in Lewis rats is the most widely used animal model for multiple sclerosis. Cyclic adenosine monophosphate (cAMP) has been associated with neuroinflammation. The aim of this study was to investigate the possible involvement of different cAMP-specific phosphodiesterase (PDE) isoenzymes by analyzing their expression in the brain of EAE rats. We found in the brain of EAE animals that there was a dramatic increase in the mRNA expression levels of the PDE4B isozyme detected around blood vessels from the spinal cord to the upper midbrain. There was a single splicing form of the 4 splice variants that are known for PDE4B: PDE4B2, which showed increased expression levels. This overexpression is localized around the blood vessels and parenchyma in infiltrating T cells and macrophages/microglia. These results support the role played by the activation of the PDE4B2 gene in the neuroinflammatory process in EAE rats.

Expression of the cGMP-specific phosphodiesterases 2 and 9 in normal and Alzheimer's disease human brains.

We studied the mRNA expression of cGMP-hydrolysing phosphodiesterases (PDEs) in selected brain areas of normal elderly people and patients with Alzheimer's disease. Using radioactive in-situ hybridization histochemistry we found a widespread distribution of the mRNA for PDE2 and PDE9, whereas no specific hybridization signal was observed for PDE5. We observed PDE2 and PDE9 mRNA in all cortical areas studied (insular cortex, entorhinal cortex and visual cortex), although to a different extent. PDE2 mRNA was high in the claustrum, whereas PDE9 mRNA was moderate. PDE2 and PDE9 mRNAs was present in the putamen. No cGMP-hydrolysing PDE expression was observed in the globus pallidus. PDE2 and PDE9 mRNA was observed in all subareas of the hippocampus; however, there were significant differences in the amount of expression. In the Purkinje and cerebellar granule cells only PDE9 expression was observed. PDE2 and PDE9 mRNA expression was not significantly different in Alzheimer's disease brains.