In AD brain, the presence of amyloid deposition, neurofibrillary tangles, activated microglia and astrocitosis may stimulate a local and a chronic inflammatory process that involves the synthesis and the release of numerous factors such as cytokines, chemokines and inflammatory mediators. However, systemic inflammation is also detectable in peripheral blood of AD as illustrated by the elevation of some acute phase proteins or cytokines.
In addition, a large number of genetic variations in genes coding for pro- or anti inflammatory molecules have been associated with the risk of dementia or cognitive decline[4, 5, 29, 30].
In the present study the distribution of MCP-1 A-2518G SNP in the promoter region of MCP-1 gene and plasma levels of MCP-1 in AD or subjects with preclinical AD were investigated.
Our findings suggested that the MCP-1 SNP promoter was not a risk factor for AD being the SNP equally distributed in AD patients and controls. Our results confirmed data from different case-controls studies reporting no association between this SNP and the risk of AD[21, 24–26]. On the other hand, a different Italian study by Pola et al. showed an increased representation of GG genotype in AD patients. Our data were not able to confirm this latter study. Differences in SNP distribution across case/controls studies might be explained by the great ethnic variability of this SNP, since the G allele is found differentially present in Caucasian, Americans or Asian population. Differences between present investigation and Pola’s study might be explained by different clinical AD or CTR selection.
Then, we studied the distribution of MCP-1 A-2815G SNP in a MCI population followed up for two years in order to evaluated the effect of this SNP on the progression of the disease. No data on the effect of this SNP in MCI/AD conversion is available in literature. The G allele frequency was slightly higher in MCI showing a further cognitive deterioration and converted to AD. However, this difference was not statistically significant. This effect might be partially ascribed to the small size of MCI population and further investigations are needed to better understand the influence of this SNP in cognitive deterioration and progression to AD.
High levels of pro-(or anti) inflammatory cytokines and chemokines have been found associated with AD. The main role of these molecules and in particular of MCP-1 is supported by the observation that this latter molecule can induce chemotaxis of monocytes and microglia, contributing to pathological gliosis associated with AD[31, 32]. Relevance of MCP-1 in AD was suggested by data showing a significantly enhanced immunoreactivity for MCP-1 in neurons, astrocytes and microglia from AD brains. Moreover, several studies reported that MCP-1 plasma or CSF levels were higher in AD patients or MCI than controls[19, 20, 31].
We found statistically differences in MCP-1 plasma levels among AD, CIND and controls, being MCP-1 levels higher in CIND than those in AD patients and/or controls.
In our study we measured MCP-1 levels by using BIO-Plex multi Cytokines platform. Our results showed that MCP-1 absolute levels, in pg/ml, from AD, CIND or CTR, were lower than those found in other reports. Different techniques for MCP-1 detection may partially explain why we did not confirm increased MCP-1 plasma levels in AD. On the other hand, our data agree with the only study that used the same detection system used by us for MCP-1 levels. Decreased level of peripheral MCP-1 levels along with increased CSF concentration of this chemokyne in AD may suggest an impaired MCP-1 turnover between these two compartments. Such an alteration may be not present in pre dementia conditions such as CIND since, increased levels of blood MCP-1 levels were observed in this population. However, further studies on a larger cohort of CIND or MCI subjects are needed to better define the role of blood MCP-1 in cognitive deterioration and AD developing and the use of blood MCP-1 as a potential marker for cognitive impairment.
MCP-1 expression might be under the control of A-2518G promoter SNP. This is supported by a study showing that the biallelic G/A polymorphism at position 2518 of the MCP-1 gene appears to influence the transcriptional activity MCP-1 gene. In particular G allele seems to be associated with a higher MCP-1 production in a dose dependent manner where GG homozygous produce more MCP-1 than that from G/A heterozygous. A previously reported study showed that MCP-1 serum levels were increased in AD patients positive for one or two G alleles. Our data did not confirm the above findings, since we did not find an increase of MCP-1 levels in AD G carrier patients. Accordingly, no effect of this SNP was observed on MCP-1 plasma levels from CIND or controls.
Our study presents some limitations due to the selection of subject with a different kind of pre-dementia condition: CIND and/or MCI. It is known that MCI, with clinical assessed symptoms and risk factors well described by Petersen RC, are likely to progress to AD at a rate of approximately 12% per year. On the other hand, subjects with CIND show heterogeneous risk factors only partially overlapping with those associated with MCI.
Data presented in our pilot study regarding the A-2518G SNP distribution and MCP-1 plasma levels in cognitive deterioration need to be replicated in a homogeneous and larger MCI population to better understand the MCP-1 role in cognitve performance and deterioration.