Changes in Chemokines and Chemokine Receptors Expression in a Mouse Model of Alzheimer's Disease

Abstract

The amyloid precursor protein plus presenilin-1 (APP/PS1) mice are a frequently-used model for Alzheimer's disease studies (AD). However, the data relevant to which proteins are involved in inflammatory mechanism are not sufficiently well-studied using the AD mouse model. Using behavioral studies, quantitative RT-PCR and Western-blot techniques, significant findings were determined by the expression of proteins involved in inflammation comparing APP/PS1 and Wild type mice. Increased GFAP expression could be associated with the elevation in number of reactive astrocytes. IL-3 is involved in inflammation and ABDF1 intervenes normally in the transport across cell membranes and both were found up-regulated in APP/PS1 mice compared to Wild type mice. Furthermore, CCR5 expression was decreased and both CCL3 and CCL4 chemokines were highly expressed indicating a possible gliosis and probably an increase in chemotaxis from lymphocytes and T cell generation. We also noted for the first time, a CCR8 increase expression with diminution of its CCL1 chemokine, both normally involved in protection from bacterial infection and demyelination. Control of inflammatory proteins will be the next step in understanding the progression of AD and also in determining the mechanisms that can develop in this disease.

Keywords: Alzheimer's disease; chemokine receptors, chemotaxis, inflammation, behavior.

Figure 1

Behavior assays. A: Exploration of two identical object (sec in 5 minutes), with no significantly differences between wild type (WT) and transgenic (TG) mice. B: Grip strength (time in 60 seconds). C: Time to cross the beam (sec). D: number of foot faults, ***p<0.01 vs. wild type mice.

Figure 2

Object location memory and object recognition memory. A: object recognition memory (discrimination index), ***p<0.01 vs. wild type mice. B: object location memory (discrimination index), *p<0.05 vs. WT mice.

Figure 3

Protein expression of A: GFAP and B: MAP-2 in cortex of APP/PS1 and WT mice. A representative immunoblot is shown in the panel. Data are mean ± SD of four independent experiments. *p<0.05 vs. WT.

Figure 4

mRNA expression of A: CCL1 and B: CCR8 in cortex of APP/PS1 and WT mice. C: Protein expression of CCR8 by Western-blot. A representative immunoblot is shown in the panel. Data are mean ± SD of four independent experiments. *p<0.05 vs. WT.

Figure 5

mRNA expression of A: CCL3, B: CCL4 and C: CCL5 and D: CCR5 by Western-blot in cortex of APP/PS1 and WT mice. A representative immunoblot is shown in the panel. Data are mean ± SD of four independent experiments. *p<0.05 vs. WT.

Figure 6

mRNA expression of A: IL-3 and B: ABCF1 in cortex of APP/PS1 and WT mice. Data are mean ± SD of four independent experiments. *p<0.05 vs. WT.

Figure 7

Inflammatory protein changes in APP/PS1 mice. The schema shows the up-regulation or down-regulation of different proteins. Pro-inflammatory mediators, such as CCL3 and CCL4, are increased. By contrast, CCR5 is down-regulated. The protein ABCF1 (a member of the superfamily of ATP-binding cassette (ABC) transporters) is increased. IL-3 (involved in the immune system) is highly expressed. Also CCR8 is increased (important for the migration of various cell types into the inflammatory sites).